Recirculating dialysate fluid circuit for measurement of blood solute species

ABSTRACT

A blood based solute monitoring system for measuring at least one blood solute species that has a first recirculation flow path in communication with a dialyzer. The first recirculation flow path is configured to allow a fluid to recirculate through a dialyzer such that the concentration of at least one solute species in the fluid becomes equilibrated to the solute species concentration of the blood compartment of the dialyzer. The blood solute monitoring system has at least one sensor to measure a fluid characteristic.

CROSS-REFERENCE

This application is a continuation of U.S. patent application Ser. No.16/154,755, filed Oct. 9, 2018, now U.S. Pat. No. 10,881,777, which is acontinuation of U.S. patent application Ser. No. 15/398,069 filed Jan.4, 2017, now U.S. Pat. No. 10,583,236, which is a divisional of U.S.patent application Ser. No. 13/836,538 filed Mar. 15, 2013, now U.S.Pat. No. 9,713,666, which claims benefit of and priority to U.S.Provisional Application No. 61/760,033 filed Feb. 1, 2013, and U.S.Provisional Application No. 61/750,760 filed Jan. 9, 2013, and thedisclosures of each of the above-identified applications are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to systems and methods for utilizing a sorbentcartridge and quantifying chemistry changes that occur as dialysatepasses through material layers of the cartridge as a means to determinesolute concentrations in the solution flowing through the cartridge. Thesystems and methods of the invention can be used in systems and methodsfor managing blood urea and quantifying urea clearance during dialysistherapy including, but not limited to, hemodialysis, hemodiafiltration,hemofiltration, and peritoneal dialysis.

BACKGROUND

Chronic Kidney Disease (CKD), also known as chronic renal disease, maybe a sudden or progressive loss in renal function. As the diseaseseverity progresses, a patient with severe renal failure develops manysymptoms that, if left untreated, eventually result in death. The mostsevere stage of CKD is End Stage Renal Disease (ESRD). ESRD, alsoreferred to as kidney failure or renal failure, is the medical conditionwherein a person's kidneys fail to sufficiently remove toxins, wasteproducts, and excess fluid, and to maintain proper electrolyte levels.

Urea is among the many waste products often found in the blood of anESRD patient's blood in an unhealthy amount. Urea is not very toxic byitself, but its level represents the levels of many other waste productsthat build up in the blood when the kidneys fail.

Kidney dialysis is a medical procedure that is performed to aid orreplace some of the kidney functions in severe renal failure.Hemodialysis, hemofiltration, hemodiafiltration, and peritoneal dialysisare all replacement therapies for patients who have lost most or all oftheir kidney function. In connection with a hemodialysis session, wasteproducts such as urea are removed from the blood. Hemodialysisartificially separates the waste products and excess water from thepatient's blood by diffusion and ultra-filtration, by circulatingthrough a machine with a special filter that removes wastes and extrafluids, with the clean blood then being returned to the body.

Urea is generally accepted to be the best marker for evaluating thelevel of uremic toxins. Dialysis procedures are therefore often aimed atreduction of urea in the blood stream. Currently, urea measurements inmost dialysis clinics are often done infrequently to lower cost.Turnaround time for these samples can be quite long, and often thepatient must be recalled for further dialysis if the percentagereduction of urea in the blood is not sufficient. In the absence of ablood check, the use of time of dialysis alone as a measure ofcompletion, especially if hemodialysis is not carried out long enough,can clearly lead to morbidity and mortality.

Moreover, these measurements often require blood sampling before andafter treatment and require time consuming chemical analyses. As aconsequence, the measurements cannot be used to determine actual ureaclearance efficiency or control the extent and duration of an individualpatient's dialysis session.

Management of patients undergoing continuous hemodialysis requires ameans of determining the adequacy of their treatment, which is typicallyreported as the unitless quantity Kt/V, where K is dialyzer clearance, tis time of hemodialysis treatment and V is body fluid volume. A simplemeasurement of blood urea nitrogen (BUN) is generally an insufficientindication of adequacy of dialysis since, for instance, a low BUN canreflect inadequate nutrition rather than sufficient urea removal bydialysis. In a patient with little or no urine output, the proteincatabolic rate (PCR) (g/day) is equal to the sum of the dialysis andstool losses of urea, protein, and amino acids. PCR is roughly equal toprotein intake when a patient is in a steady state with a relativelyconstant pre-dialysis BUN. As such, BUN is largely reflective of patientdiet rather than the adequacy of dialysis treatment. Monitoring thepatient's symptoms alone is also insufficient, since the combination ofdialysis plus with other treatments (e.g. erythropoietin to increase redblood cell count) can eliminate most uremic symptoms although thepatient may be underdialyzed.

In accessing the adequacy of hemodialysis, blood tests for hemodialysispatients are typically, however, performed only on a monthly basis. Manyfactors can compromise the effective clearance achieved during adialysis session. These factors include blood access recirculation,access connection errors, dialyzer clotting, blood flow errors, dialysissession interruptions, and dialyzer variability. However, monthly orperiodic testing is inadequate to determine if effective clearance isachieved by any individual dialysis treatment.

A number of approaches have been described in the art for determiningBUN and urea content:

U.S. Pat. No. 3,776,819 describes a method to measure BUN by means of acation sensitive electrode having a urease layer on its surface. Theelectrode configured in this manner is then placed in a solutioncontaining urea and a millivolt signal is analyzed to determine the ureaconcentration.

U.S. Pat. No. 5,308,315 describes an enzymatic urease sensor to measurethe urea concentration electrometrically in spent dialysate, combinedtogether with measured flows for arterial blood, venous blood, anddialysate to calculate the arterial BUN by a method based on principleof solute mass balance across the dialyzer. The enzymatic urease sensingmethod used is a modified Nova 12 chemistry analyzer for NovaBiomedical, Waltham, Mass. The arterial BUN measurements are used tomeasure URR for purposes of determining when the prescribed dialysisdose is completed.

U.S. Pat. No. 5,849,179 describes a method for obtaining a pre-dialysisBUN measurement by equilibrating the dialysate urea concentration to theblood urea concentration before the start of dialysis. The method ofequilibration is to start blood flow through the primed dialyzer whilepreventing flow of the dialysate until the concentrations between bloodand dialysate are equilibrated. The equilibrated sample is then analyzedby passing the sample to an ammonium sensitive electrode covered by acap containing urease.

U.S. Pat. No. 5,662,806 further describes how a continuing sequence ofnon-equilibrated samples of spent dialysate with urea concentrationmeasured by this sensor system can be used to monitor the progress of adialysis dose with quantification of Kt/V and URR.

U.S. Pat. No. 5,858,186 describes an electrochemical sensor thatquantifies urea concentration by measuring pH changes in an aqueousenvironment that occur when enzyme catalyzed hydrolysis of urea occurs.

European Patent 0 614 081 B1 describes a method and apparatus thatpasses ultrafiltrate from a hemofilter through a urease containingreactor. Inductive type conductivity sensors are positioned in the fluidcircuit before the urease reactor inlet and after the urease reactoroutlet. The difference in conductivity is used to determine the ureaconcentration of the ultrafiltrate. The BUN is determined in this methodbecause ultrafiltrate has the same urea concentration as the arterialblood.

U.S. Pat. Nos. 6,114,176 and 6,521,184 describe a method and apparatusto measure urea in spent dialysate by measuring the conductivity of thedialysate before and after passing through a column containing urease.The method discloses infusion of carbon dioxide into the dialysate as abuffer to maximize conversion of urea to the ionic byproducts ammoniumand bicarbonate so that the maximum conductivity signal is obtained. Useof single or dual conductivity sensors is discussed.

U.S. Pat. No. 6,666,840 describes a method and apparatus for determiningwaste products in dialysate, including urea by means of measuringabsorption of ultraviolet light.

U.S. Pat. No. 7,326,576 describes the use of Raman spectroscopy tomeasure urea concentration in blood through the tubing of theextracorporeal circuit.

US patent application publication 2011/0163034 describes measurement ofurea in spent dialysate by means of UV sensing or other urea sensors andmethods to determine the K/V slope and assess whether the dialysistherapy session is proceeding according to the prescribed dialysis dose.

There is a need for determining BUN and urea content for hemodialysispatients more frequently than on a monthly basis. There is also a needfor assessing the adequacy of dialysis during treatment. There is a needfor improved methods and devices for assessing and monitoring theeffective clearance achieved during a given dialysis session. There is aneed for obtaining a measured clearance of waste products during eachdialysis session and determining if delivery of less or more than theprescribed dialysis clearance has occurred.

In particular, there is a need to provide a blood based solutemonitoring system for measuring at least one blood solute species,wherein a first recirculation flow path can be in fluid communicationwith a dialyzer and can be configured to allow a fluid to recirculatethrough a dialyzer such that the concentration of at least one solutespecies in the fluid becomes equilibrated to the solute speciesconcentration of the blood in a blood compartment of the dialyzer.

SUMMARY OF THE INVENTION

The present invention relates to a blood based solute monitoring systemfor measuring at least one blood solute species. In any embodiment, afirst recirculation flow path can be in fluid communication with adialyzer. In any embodiment, the first recirculation flow path can beconfigured to allow a fluid to recirculate through a dialyzer such thatthe concentration of at least one solute species in the fluid becomesequilibrated to the solute species concentration of the blood in a bloodcompartment of the dialyzer. In any embodiment, the blood solutemonitoring system can have at least one sensor to measure a fluidcharacteristic.

In any embodiment, the blood based solute monitoring system can have asecond flow path that passes the fluid through the dialyzer. In anyembodiment, the at least one solute species in the fluid does not becomeequilibrated with the solute species in the blood in the bloodcompartment of the dialyzer.

In any embodiment, the blood based solute monitoring system can have theat least one solute species in the fluid in the second flow path notbeing equilibrated with solute species in the blood in the bloodcompartment of the dialyzer.

In any embodiment, the blood based solute monitoring system can have thesecond flow path being a sorbent regenerated dialysate flow path.

In any embodiment, the blood based solute monitoring system can have thesecond flow path being a controlled compliant flow path.

In any embodiment, the blood based solute monitoring system can have thefirst recirculation flow path having a small volume and a control valvefor selectively metering fluid in and out of the first recirculationflow path.

In any embodiment, the blood based solute monitoring system can have thefirst recirculation flow path being in fluid communication with a REDYsystem.

In any embodiment, the blood based solute monitoring system can havedialysate being recirculated through the sorbent cartridge and not thedialyzer to create a baseline concentration and directed through thedialyzer and a solute concentration profile can be measured and used todetermine the solute clearance through the dialyzer.

In any embodiment, the blood based solute monitoring system can have theequilibration time taking less than any one of 10 minutes, 7 minutes, 5minutes, 3 minutes, 2 minutes, and 1 minute.

In any embodiment, the blood based solute monitoring system can have acontrol mechanism to decrease equilibration time by increasing dialysateand/or blood flow during fluid flow through the first recirculation flowpath.

In any embodiment, the blood based solute monitoring system can have acontrol mechanism to decrease equilibration time by continuing toperform ultrafiltration during fluid flow through the firstrecirculation flow path with or without increased rate of fluid flows.

In any embodiment, the blood based solute monitoring system can have thevoid volume of the components and conduits that make up the firstrecirculation flow path being less than a volume from the groupconsisting of 1.0 L, 0.5 L, 0.4 L, 0.3 L, 0.2 L, and 0.1 L.

In any embodiment, the blood based solute monitoring system can have avalve. In any embodiment, operation of the valve can determine whetherthe fluid flows through the first recirculation flow path or the secondflow path.

In any embodiment, the blood based solute monitoring system can have apump. In any embodiment, operation of the pump can cause the fluid toflow through the first recirculation flow path.

In any embodiment, the blood based solute monitoring system can have thesensor being an ion selective sensor.

In any embodiment, the blood based solute monitoring system can have atleast two sensors to measure a fluid characteristic.

In any embodiment, the blood based solute monitoring system can have thesensor being a conductivity sensor.

In any embodiment, the blood based solute monitoring system can have thesensor being any one of a potassium sensor, a bicarbonate sensor, or anammonia sensor.

In any embodiment, the blood based solute monitoring system can have theconductivity sensor being used to determine when equilibration with theblood has been achieved.

In any embodiment, the blood based solute monitoring system can have theconductivity sensor being used as a measure of the sodium concentrationof the blood.

In any embodiment, the blood based solute monitoring system can have thesodium concentration being measured at the start of a therapy session todetermine a pre-dialysis blood sodium concentration of a subject andbeing used to profile the dialysate sodium concentration during thetherapy session.

In any embodiment, the blood based solute monitoring system can have thesensor being a pH sensor.

In any embodiment, the blood based solute monitoring system can have theblood solute monitoring system being in fluid communication with acontrolled compliant flow path.

In any embodiment, the blood based solute monitoring system can have asorbent system for regenerating the dialysate and returning thedialysate to the dialyzer.

In any embodiment, the blood based solute monitoring system can havefluid flowing in the first recirculation flow path through the dialyzerthat does not pass through one or more material layer of a sorbentsystem.

In any embodiment, the blood based solute monitoring system can have atleast one material layer contains one or more selected from aurease-containing material, alumina, zirconium phosphate, zirconiumoxide, a divalent cation, activated carbon, and mixtures thereof.

In any embodiment, the blood based solute monitoring system can have atleast one material layer containing urease present in the firstrecirculation flow path.

In any embodiment, the blood based solute monitoring system can havedialysate flowing in the first recirculation flow path contacting adefined sequence of material layers within the sorbent system.

In any embodiment, the blood based solute monitoring system can have anelectrolyte bolus injector.

In any embodiment, the blood based solute monitoring system can have theelectrolyte bolus injector being located in the first recirculation flowpath at a position downstream from a dialysate outlet of the dialyzerand upstream of the sorbent system, and the system monitoring fluid atone or more positions in the first recirculation flow path selected fromthe group consisting of: a first position downstream from the dialyzeroutlet and downstream from the electrolyte bolus injector where thefluid has not contacted any material layer of the sorbent system; asecond position where the fluid has contacted a urease-containingmaterial layer; a third position where the fluid has contacted anadditional material layer that is not a urease-containing materiallayer; and a fourth position in fluid communication with dialysateeluted from an outlet of the dialyzer and positioned upstream from theelectrolyte bolus injector.

In any embodiment, the blood based solute monitoring system can have thefluid at the second position having only contacted the urease-containingmaterial layer.

In any embodiment, the blood based solute monitoring system can measurethe conductivity of the fluid at one or more positions within thecontrolled compliant flow path.

In any embodiment, the blood based solute monitoring system can measurethe conductivity of the fluid at one or more positions within thesorbent system.

In any embodiment, the blood based solute monitoring system can have oneor more selected from the group consisting of: an acid feed supplied tothe controlled compliant flow path; a bicarbonate feed; and a waterfeed.

In any embodiment, the blood based solute monitoring system can have asorbent system having a plurality of material layers within the sorbentsystem. In any embodiment, dialysate exiting a dialyzer can be conveyedthrough the sorbent system.

In any embodiment, the blood based solute monitoring system can have acontrolled compliant flow path circulating the dialysate between adialyzer and the sorbent system.

In any embodiment, the blood based solute monitoring system can formpart of a hemodialysis or hemodiafiltration system.

The present invention also relates to a method for measuring the soluteconcentration of at least one blood solute species, including the stepsof: switching fluid flow in a fluid therapy device from a first flowpath to a dialyzer recirculation flow path; equilibrating the dialysatewith a blood side of the dialyzer; and measuring the soluteconcentration in the dialysate that has been equilibrated with the bloodside of the dialyzer.

In any embodiment, the method for measuring the solute concentration ofat least one blood solute species can include the step of switching flowfrom the dialyzer recirculation flow path to the first flow path forcontinuing with a fluid therapy.

The present invention also relates to a method for measuring BUN,including the steps of: switching fluid flow in a fluid therapy devicehaving a sorbent system and a dialyzer from a first flow path to asorbent bypass fluid path; recirculating the dialysate through thedialyzer; and equilibrating the dialysate with blood in the blood sideof the dialyzer.

In any embodiment, the method for measuring BUN can include switchingthe fluid flow from the sorbent bypass fluid path to a non-bypass path;and measuring an ammonium ion concentration of the equilibrateddialysate after contacting urease in the sorbent system.

In any embodiment, the method for measuring BUN can include the step ofcontinuing with dialysis.

The present invention also relates to a method for measuring the soluteconcentration of at least one blood solute species, including the stepsof: switching fluid flow in a fluid therapy device having a sorbentsystem and a dialyzer from a first flow path to a sorbent bypass fluidpath; recirculating the dialysate through the dialyzer; andequilibrating the dialysate with blood in the blood side of thedialyzer; and measuring the conductivity of the equilibrated dialysatebefore the dialysate has contacted a predetermined layer or sequence oflayers to provide a first conductivity value; and switching the fluidflow from the sorbent bypass fluid path to cause the equilibrateddialysate to contact a predetermined material layer or sequence ofmaterial layers in the sorbent system; and measuring the conductivity ofthe equilibrated dialysate after it has contacted the predeterminedmaterial layer or sequence of material layers to provide a secondconductivity value.

In any embodiment, the method for measuring the solute concentration ofat least one blood solute species can include the step of determining asolute concentration according to a predetermined relationship betweenconductivity and solute concentration.

In any embodiment, the method for measuring the solute concentration ofat least one blood solute species can have the solute concentrationbeing based upon a difference of the second conductivity value and thefirst conductivity value.

In any embodiment, the method for measuring the solute concentration ofat least one blood solute species can include the step of continuingwith dialysis.

In any embodiment, the method for measuring the solute concentration ofat least one blood solute species can have the contacted materialcontaining urease, the blood solute concentration measured being BUN andthe sensed fluid characteristic being the conductivity of the fluid.

In any embodiment, the method for measuring the solute concentration ofat least one blood solute species can include measuring the conductivityof a second non-equilibrated dialysate before contacting a ureasecontaining material to provide a third conductivity value; measuring theconductivity of the second non-equilibrated dialysate after contacting aurease containing material to provide a fourth value; and determiningthe effective urea clearance of the dialyzer from the first, second,third and fourth conductivity values.

In any embodiment, the method for measuring the solute concentration ofat least one blood solute species can include one or more determinationsof the effective clearance of a dialyzer. In any embodiment, thesedeterminations can be used to monitor the performance of a therapysession.

The present invention also relates to a method to measure BUN, includingmeasuring a first conductivity value of a dialysate flowing from anoutlet of a dialyzer not having contacted a urease containing materiallayer of a sorbent system; measuring a second conductivity value of thedialysate flowing from the outlet of a dialyzer after the fluid hascontacted a urease containing material layer of a sorbent system;intermittently providing an electrolyte bolus or diluent to thedialysate flow path and measuring a bolus conductivity of the dialysatepassing to the dialyzer to provide a third conductivity value; measuringa bolus conductivity of the dialysate passing from the dialyzer toprovide a fourth conductivity value; and determining the effectiveclearance of the dialyzer from the third and fourth conductivity values.

In any embodiment, the method to measure BUN can include determining theBUN from the effective clearance of the dialyzer from the first andsecond conductivity values.

In any embodiment, the method to measure BUN can include determining theblood concentration of a solute from the said effective clearance of thedialyzer from the first and second equilibrated conductivity values.

In any embodiment, the method of the blood based solute monitoringsystem for measuring at least one blood solute species can include thestep of determining the urea content of the dialysate flowing from thedialyzer based at least in part on the difference in conductivitybetween at least a first and second sensor values.

In any embodiment, the method of the blood based solute monitoringsystem for measuring at least one blood solute species can include thedialysate contacting the plurality of materials in a sequential order.

In any embodiment, the method to measure BUN can have the one or moresorbent cartridges having an ion exchange resin selective for calciumions and magnesium ions and releasing hydrogen ions in exchange.

In any embodiment, the method to measure BUN can include a thirdconductivity value of the equilibrated dialysate that has contacted anadditional material layer is not contacted by the fluid of the first orsecond conductivity value; and determining the blood soluteconcentration of at least a second blood solute from either the secondand third conductivity values or the first and third conductivityvalues.

In any embodiment, the method to measure BUN can include calculating oneof the selected measures BUN (blood urea nitrogen), URR (urea reductionratio), Kt/V, eKt/V (equilibrated Kt/V), and PCR (protein catabolicrate), wherein k stands for dialyzer clearance rate, t stands fordialysis time, and V stands for volume of distribution of urea.

In any embodiment, URR can be determined by calculating a first BUNprior to dialysis and a second BUN post dialysis.

In any embodiment, Kt/V, eKt/V and PCR can each be determined based on adifference between the first and second conductivity values.

In any embodiment, the method to measure BUN can include determining thelevel or concentration of a solute selected from the group of K, Mg, Ca,pH, bicarbonate, and glucose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a dialysate regeneration cartridge operating in accordancewith certain embodiments.

FIG. 2 shows a dialysate regeneration unit having dialysate conductivitysensors operating in accordance with certain embodiments.

FIG. 3 shows a dialysate regeneration unit having a dialysateconductivity sensor in fluid communication with multiple sampling flowstreams operating in accordance with certain embodiments.

FIG. 4 shows a dialysate regeneration unit having multiple regenerationsegment bypass conduits and a conductivity sensor operating inaccordance with certain embodiments.

FIG. 5 shows a dialysate regeneration unit having a dialysateconductivity sensor in fluid communication with multiple sampling flowstreams operating in accordance with certain embodiments.

FIG. 6 shows a dialysate regeneration unit having a dialysateconductivity sensor in fluid communication with multiple sampling flowstreams operating in accordance with certain embodiments for determininga differential conductivity.

FIG. 7 shows a dialysate regeneration unit having a dialysateconductivity sensor in fluid communication with four sampling flowstreams operating in accordance with certain embodiments.

FIG. 8 shows a dialysate regeneration unit having a dialysateconductivity sensor in fluid communication with multiple sampling flowstreams and an infusate injector.

FIG. 9 shows a dialysate regeneration unit having a dialysateconductivity sensor in fluid communication with multiple sampling flowstreams operating with a highly-selective ion exchange resin.

FIG. 10 shows a dialysate regeneration unit having a dialysateconductivity sensor in fluid communication with multiple sampling flowstreams operating with a regeneration unit bypass flow path.

FIG. 11 shows a dialysate regeneration unit having a dialysateconductivity sensor in fluid communication with multiple sampling flowstreams operating for use in hemofiltration.

FIG. 12 shows a dialysate regeneration unit having a dialysateconductivity sensor in fluid communication with multiple sampling flowstreams operating for use in hemodiafiltration.

FIG. 13 shows a dialysate regeneration unit having a dialysateconductivity sensor in fluid communication with multiple sampling flowstreams operating for use in peritoneal dialysis.

FIG. 14 shows a dialysate regeneration unit with an ion-specificexchange resin and having a dialysate conductivity sensor in fluidcommunication with multiple sampling flow streams operating inaccordance with certain embodiments.

FIG. 15 shows a dialysate regeneration unit having a dialysateconductivity sensor in fluid communication with multiple sampling flowstreams in an alternative configuration connected to a water source.

FIG. 16 shows a dialysate regeneration unit having a bypass flow looparound a sorbent cartridge.

FIG. 17 shows a dialysate regeneration unit having a bypass flow loopand a recirculating flow loop around a sorbent cartridge.

FIG. 18 shows a dialysate regeneration unit having a bypass flow looparound a sorbent cartridge and a bypass flow loop around a dialyzer.

FIG. 19 shows a dialysis flow diagram for a single-pass system with abypass flow loop around a dialyzer.

FIG. 20 is a graph showing the effect of a 6 liter dialysate volume onequilibration time between dialysate and blood.

FIG. 21 is a graph showing the effect of a 0.5 liter dialysate volume onequilibration time between dialysate and blood.

FIG. 22 is a graph showing the effect of various dialysate volumes onthe concentration change of dialysate over time during equilibration.

FIG. 23 is a graph showing the effect of dialysate flow rate onequilibration time between dialysate and blood.

FIG. 24 shows a sorbent cartridge with built in electrodes for measuringconductivity perpendicular to the central axis.

FIG. 25 shows a sorbent cartridge with built in electrodes for measuringconductivity parallel to the central axis.

FIG. 26 shows a sorbent cartridge with built in electrodes for measuringconductivity parallel to the central axis over a distance spanning asorbent material layer.

FIG. 27 shows a sorbent cartridge with built in electrodes for measuringconductivity parallel to the central axis over a distance spanningmultiple sorbent material layers.

FIG. 28 shows a sorbent cartridge with built in mesh electrodes formeasuring conductivity parallel to the central axis over a distancespanning multiple sorbent materials.

FIG. 29 shows different electrode designs.

FIG. 30 shows a sorbent cartridge with electrodes built into the wall ofthe sorbent cartridge for measuring conductivity.

Like reference numbering between FIG.'s represents like features andelements.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the relevant art. The definitions provided hereinshould not be rigidly construed without taking into account the contextand other ascribed meanings provided, or by their use, in other parts ofthe specification, claims, and drawings.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “substantially” refers to an extent of similarity between anytwo given values that is at least 75 percent, 80 percent, 85 percent, 90percent, 95 percent, or 99.9 percent, the given values optionallyincluding values in weight, height, length, area, temperature, angledimensions, among others.

The term “acid or base equivalents” refers to an equivalent acid or basedonating or accepting an equal number of moles of hydrogen or hydroniumions per mole of the acid to which the equivalent acid is being equated,or mole of hydroxide ions to which the equivalent base is being equated.

The term “cation infusate pump” historically known as an “acidconcentrate pump” in dialysis systems refers to a pump that serves thefunction to move or control the flow of a fluid to and/or from areservoir having a substance that contains at least one cation species,such as calcium, magnesium and potassium ions. In the present invention,the historically used term of “acid concentrate pump” is used.

The term “acid feed” refers a state of fluid communication that enablesan acid solution to be obtained from an acid source and connected orfeed into a receiving source or flow path.

An “acid” can be either an Arrhenius acid, a Brønsted-Lowry acid, or aLewis acid. The Arrhenius acids are substances or fluids which increasethe concentration of hydronium ions (H₃O⁺) in solution. TheBrønsted-Lowry acid is a substance which can act as a proton donor.Lewis acids are electron-pair acceptors.

The term “activated carbon” may refer to a porous carbon material havinga surface area greater than 500 m² per gram. Activated carbon can becapable of absorbing several species including heavy metals such aslead, mercury, arsenic, cadmium, chromium and thallium among others,oxidants such as chlorine and chloramines, fluoride ions, and wastespecies such as phosphate and certain nitrogen-containing waste speciessuch as creatinine and uric acid.

The terms “administering,” “administer,” “delivering,” “deliver,”“introducing,” and “introduce” can be used, in context, interchangeablyto indicate the introduction of water or a dialysate having an alteredconcentration of at least one component, including electrolytes andalkali and/or alkali earth ions, to a patient in need thereof, and canfurther mean the introduction of water, any agent or alkali and/oralkali earth ions to a dialysate or dialysis circuit where such water,agent or alkali and/or alkali earth ion will enter the blood of thepatient by diffusion, transversal of a diffusion membrane or othermeans.

The term “air trap” refers to a structure for separating a gas from amixture of a gas and a liquid or any other separation means known in theart. An air trap can include a hydrophobic membrane for allowing gasesto pass and for preventing the passage of water.

The term “albumin sieving coefficient” can be used to describe theamount of albumin that will cross a membrane.

The terms “ammonia sensing module” and “ammonia detector” refer to aunit that performs all or part of the function to detect a predeterminedlevel of, or measure a concentration of, ammonia and/or ammonium ions ina fluid.

The term “anion exchange membrane” refers to a positively chargedmembrane, which allows negatively charged ions (anions) to pass through.

The term “anticoagulant” is a substance that prevents or delays theclotting of blood, such as heparin, Fragmin®, and sodium citrate.

The term “atmospheric pressure” refers to the local pressure of air inthe environment in proximity to the system at the time that the systemis operating.

The term “base concentrate pump” refers to a device that performs workon a fluid solution to cause fluid flow to control the volume transferof a basic or alkaline solution into a circuit.

The term “base concentrate reservoir” refers to a vessel or container,optionally accessible by a pump that contains a variable amount of abasic or alkaline fluid solution.

The term “base module” refers to a basic unit of an apparatus forhemodialysis, hemodiafiltration, or hemofiltration that incorporates oneor more fluid pathways. Exemplary, non-limiting components that can beincluded in the base module include conduits, valves, pumps, fluidconnection ports, sensing devices, a controller and a user interface.The base module can be configured to interface with reusable ordisposable modules of the apparatus for hemodialysis, hemodiafiltration,or hemofiltration to form at least one complete fluid circuit, such as adialysis, cleaning, disinfection, priming or blood rinse back circuit.

A “base” can be either a substance that can accept hydrogen cations(protons) or more generally, donate a pair of valence electrons. Asoluble base is referred to as an alkali if it contains and releaseshydroxide ions (OH—) quantitatively. The Brønsted-Lowry theory definesbases as proton (hydrogen ion) acceptors, while the more general Lewistheory defines bases as electron pair donors, allowing other Lewis acidsthan protons to be included. The Arrhenius bases act as hydroxideanions, which is strictly applicable only to alkali.

The term “base feed” refers a state of fluid communication that enablesa base solution to be obtained from a base source and connected or feedinto a receiving source or flow path.

The term “bicarbonate buffer component” refers to any compositioncontain bicarbonate (HCO₃ ⁻) ion or a conjugate acid of bicarbonate ionin any amount, proportion or pH of the composition. The bicarbonatebuffering system is an important buffer system in the acid-basehomeostasis of living things, including humans. As a buffer, it tends tomaintain a relatively constant plasma pH and counteract any force thatwould alter it. In this system, carbon dioxide (CO2) combines with waterto form carbonic acid (H₂CO³), which in turn rapidly dissociates to formhydrogen ions and bicarbonate (HCO₃ ⁻) as shown in the reactions below.The carbon dioxide—carbonic acid equilibrium is catalyzed by the enzymecarbonic anhydrase; the carbonic acid—bicarbonate equilibrium is simpleproton dissociation/association and needs no catalyst.CO₂+H₂O⇄H₂CO₃⇄HCO₃ ⁻+H⁺Any disturbance of the system will be compensated by a shift in thechemical equilibrium according to Le Chatelier's principle. For example,if one attempted to acidify the blood by dumping in an excess ofhydrogen ions (acidemia), some of those hydrogen ions will associatewith bicarbonate, forming carbonic acid, resulting in a smaller netincrease of acidity than otherwise.

The term “bicarbonate buffer concentrate” refers to a bicarbonate (HCO₃⁻) buffer component composition at a higher concentration than found atnormal physiological levels that can be used to for instants toreadjusted the pH of the dialysate (see also definition of bicarbonatebuffer component relating to its use).

The term “bicarbonate cartridge” refers to a container that can be astand-alone container or alternatively can be integrally formed with anapparatus for hemodialysis, hemodiafiltration, or hemofiltration. Thebicarbonate cartridge can store a source of buffering material, such assodium bicarbonate, and can be configured to interface with at least oneother functional module found in systems for hemodialysis,hemodiafiltration, or hemofiltration. For example, the bicarbonatecartridge can contain at least one fluid pathway and include componentssuch as conduits, valves, filters or fluid connection ports. Thebicarbonate cartridge can be disposable or be consumable wherein thecartridge is recharged upon depletion. Specifically, the term“bicarbonate consumables container” refers to an object or apparatushaving or holding a material in solid and/or solution form that is asource of bicarbonate, such as sodium bicarbonate, that is depletedduring operation of the system. The object or apparatus may be singleuse, or may be replenished and used multiple times, for example, byrefilling the object to replace the consumed material.

The term “bicarbonate feed” refers to fluid solution introduced intopart of the dialysis or ultrafiltrate system. For example a “bicarbonatefeed” is a conduit that contains a bicarbonate buffer concentrate thatis used to readjust the pH of the dialysate.

The term “bidirectional pump” refers to a device configured to performwork on a fluid to cause the fluid to flow alternatively in either oftwo opposing directions.

A “biocompatible material” is a material that has the ability tointerface with living biological tissues with an acceptable hostresponse in any of specific medical systems, methods of treatment ordelivery contemplated herein. The biocompatible material can consist ofsynthetic, natural or modified natural polymers intended to contact orinteract with the biological systems during application of any of theinventions contained herein.

The term “bipolar electrodialysis system” refers to an electrochemicalseparation process in which ions are selectively transferred through abipolar membrane.

The term “bipolar membrane” refers to a membrane formed by bonding ananion exchange and a cation exchange membrane together wherein themembranes result in the dissociation of water into hydrogen ions. Theanion- and cation-exchange membranes can either be bound togetherphysically or chemically such that the bipolar membrane has a thininterface where water diffuses into the membrane from outside aqueoussalt solutions.

The term “blood access connection” refers to a junction or aperturethrough which the blood of a subject is conveyed to or from anextracorporeal circuit. Commonly, the blood access connection is madebetween a terminal end of a conduit of an extracorporeal circuit and theterminal end of a catheter or fistula needle that is distal to thesubject receiving therapy. A subject may have more than one blood accessconnection when receiving therapy. In the case of two blood accessconnections they can be referred to as an arterial blood accessconnection and a venous blood access connection.

The term “blood solute” refers to a substance dissolved, suspended, orpresent in blood or dialysate.

The term “bolus” refers to an increase (or at times a decrease) oflimited duration in an amount or concentration of one or more solutes,for example sodium, glucose and potassium, or a solvent, for examplewater, such that the concentration of a solution is changed. The term“bolus” includes delivery of solute and/or solvent to the dialysatefluid path such that it is delivered to the blood of a subject viadiffusion and/or convection across a dialysis membrane such that theamount or concentration in the subject is increased or decreased. A“bolus” may also be delivered directly to the extracorporeal flow pathor the blood of a subject without first passing through the dialysismembrane.

The term “bottled water” refers to water that may be filtered orpurified and has been packaged in a container. Bottled water can includewater that has been packaged and provided to a consumer as drinkingwater. The term “breakthrough capacity” refers to the amount of solute asorbent material can remove until breakthrough occurs. Breakthroughoccurs when the concentration of a certain solute exiting a regenerationmodule becomes non-zero.

The terms “bubble detector”, “bubble sensor”, “gas detector” and “airdetector” refer to a device that can detect the presence of a void, voidspace, or gas bubble in a liquid.

The term “buffer conduit flow path” refers to a fluid flow path in fluidcommunication with a stored source of a buffering material, such asbicarbonate.

The term “buffer source” refers to a stored material, such asbicarbonate, acetate or lactate that provides buffering.

The terms “buffer source container” and “buffer source cartridge” referto objects that have or hold one or more materials, in solid and/orsolution form, that are a source of buffering, for example abicarbonate, a lactate, or acetate; and the object further having atleast one port or opening to allow at least a portion of the bufferingmaterial to be released from the object during operation of the system.

The term “blood based solute monitoring system” refers to a system formonitoring a substance dissolved or suspended or present in blood ordialysate.

The term “blood rinse back” refers to returning the blood from adialyzer and/or extracorporeal circuit to a subject, normally atconclusion of a therapy session and prior to disconnecting or removingthe subject's blood access connection or connections. The procedure caninclude conveying a physiologically compatible solution through theextracorporeal circuit to push or flush the blood from theextracorporeal circuit to the subject via the subject's blood accessconnection or connections.

The terms “bypass circuit” “bypass conduit,” “bypass flow path,” “bypassconduit flow path” and “bypass” refer to a component or collection ofcomponents configured or operable to create an alternate fluid pathwayto convey a fluid around one or more other components of a fluid circuitsuch that at least a portion of the fluid does not contact or passthrough the one or more other components. At times the term “shunt” maybe used interchangeable with the term “bypass.” When any of the above“bypass” terms listed in this paragraph are used in context as beingpart of a controlled compliant system, then the relevant referenced“bypass” has the proper characteristics as to operate within acontrolled compliant system as defined herein.

The term “bypass regulator” refers to a component such as valve that candetermine the amount of fluid that can pass through a by-pass portion ofa fluid circuit.

The term “capacitive deionization” refers to a process for directlyremoving salts from solution by applying an electric field between twoelectrodes.

The term “cartridge” refers to a compartment or collection ofcompartments that contains at least one material used for operation ofthe system of the present invention.

The term “cassette” refers to a grouping of components that are arrangedtogether for attachment to, or use with the device, apparatus, orsystem. One or more components in a cassette can be any combination ofsingle use, disposable, consumable, replaceable, or durable items ormaterials.

The term “cation exchange membrane” refers to a negatively chargedmembrane, which allows positively charged ions (cations) to pass. Byconvention, electrical current flows from the anode to the cathode whena potential is applied to an electrodialysis cell. Negatively chargedanions such as chloride ions are drawn towards the anode, and positivelycharged cations such as sodium ions are drawn towards the cathode.

The term “cation infusate source” refers to a source from which cationscan be obtained. Examples of cations include, but are not limited to,calcium, magnesium and potassium. The source can be a solutioncontaining cations or a dry composition that is hydrated by the system.The cation infusate source is not limited to cations and may optionallyinclude other substances to be infused into a dialysate or replacementfluid, non-limiting examples can be glucose, dextrose, acetic acid andcitric acid.

The term “cation concentrate reservoir” refers to an object having orholding a substance that is comprised of at least one cation, forexample calcium, magnesium, or potassium ions.

The terms “communicate” and “communication” include, but are not limitedto, the connection of system electrical elements, either directly orremotely, for data transmission among and between said elements. Theterms also include, but are not limited, to the connection of systemfluid elements enabling fluid interface among and between said elements.

The terms “conduit”, “conduit” or “flow path” refer to a vessel orpassageway having a void volume through which a fluid can travel ormove. A conduit can have a dimension parallel to the direction of travelof the fluid that is significantly longer than a dimension orthogonal tothe direction of travel of the fluid.

The term “central axis” refers to (a) a straight line about which a bodyor a geometric figure rotates or may be supposed to rotate; (b) astraight line with respect to which a body or figure issymmetrical—called also axis of symmetry; (c) a straight line thatbisects at right angles a system of parallel chords of a curve anddivides the curve into two symmetrical parts; or (d): one of thereference lines of a coordinate system.

The term “chelating resins” refers to a class of resins that interactsand selectively binds with selected ions and ligands (the process isreferred to as chelation). According to IUPAC, the formation or presenceof two or more separate coordinate bonds.

The term “chronic kidney disease” (CKD) refers to a conditioncharacterized by the slow loss of kidney function over time. The mostcommon causes of CKD are high blood pressure, diabetes, heart disease,and diseases that cause inflammation in the kidneys. CKD can also becaused by infections or urinary blockages. If CKD progresses, it canlead to end-stage renal disease (ESRD), where the kidneys fail tofunction at a sufficient level.

The term “citric acid” refers to an organic acid having the chemicalformula C₆H₈O₇, and may include anhydrous and hydrous forms of themolecule, and aqueous solutions containing the molecule.

The term “cleaning and/or disinfection concentrate” refers to a drysubstance, or concentrated solutions containing at least one materialfor use in cleaning and/or disinfection of an apparatus.

The term “cleaning and/or disinfection solution” refers to a fluid thatis used for the purpose of removing, destroying or impairing at least aportion of at least one contaminant. The contaminant may be organic,inorganic or an organism. The fluid may accomplish the purpose bytransmission of thermal energy, by chemical means, flow friction or anycombination thereof.

The terms “cleaning manifold” and “cleaning and disinfection manifold”refer to an apparatus that has fluid connection ports and one or morefluid pathways, or fluid port jumpers, that, when connected to jumperedports of a base module, create one or more pathways for fluid to beconveyed between the jumpered ports of the base module. A cleaningmanifold may be further comprised of additional elements, for examplevalves and reservoirs.

The term “container” as used herein is a receptacle that may be flexibleor in-flexible for holding fluid or solid, such as for example a spentdialysate fluid, or a sodium chloride or sodium bicarbonate solution orsolid.

The terms “common container,” “common cartridge,” or “common reservoir,”and the like refer to an object or apparatus that can hold more than onematerial; however, the time of holding more than one material may or maynot necessarily be at the same time. The material(s) may be in solidand/or solution forms and may be held in separate compartments withinthe object or apparatus.

The term “common fluid inlet port” refers to an opening or aperturethrough which all fluid first passes to enter an object, apparatus orassembly.

The term “common fluid outlet port” refers to an opening or aperturethrough which all fluid passes to exit an object, apparatus or assembly.

The terms “communicate” and “communication” include, but are not limitedto, the connection of system electrical elements, either directly orremotely, for data transmission among and between said elements. Theterms also include, but are not limited, to the connection of systemfluid elements enabling fluid interface among and between said elements.

The terms “component” and “components” refer to a part or element of alarger set or system. As used herein, a component may be an individualelement, or it may itself be a grouping of components that areconfigured as a set, for example, as a cassette or a cleaning and/ordisinfection manifold.

The term “comprising” includes, but is not limited to, whatever followsthe word “comprising.” Thus, use of the term indicates that the listedelements are required or mandatory but that other elements are optionaland may or may not be present.

The term “concentrate pump” refers to a device that can perform work ona fluid solution to cause the fluid flow and can actively control thetransfer of fluid volume such as an infusate or an acid concentrate,base concentrate, or buffer concentrate into a circuit.

The terms “concentrate flow channel,” “concentrate flow loop,”“concentrate stream,” refer to a fluid line in which ion concentrationis increased during electrodialysis.

The terms “conditioning conduit flow path” and “conditioning flow path”refer to a fluid pathway, circuit or flow loop that incorporates asource of a conditioning material, for example a sodium salt orbicarbonate.

The term “conditioning flow path inlet” refers to a location on aconditioning flow path where fluid enters the conditioning flow path.

The term “conditioning flow path outlet” refers to a location on aconditioning flow path where fluid exits the conditioning flow path.

The terms “conductivity meter,” “conductivity sensor,” “conductivitydetector”, conductivity electrode or the like, refer, in context, to adevice for measuring the electrical conductance of a solution and/or theion, such as a sodium ion, concentration of a solution. In specificexamples, the conductivity sensor, meter, or conductor can be directedto a specific ion such as sodium and be referred to as a “sodiumelectrode,” “sodium sensor,” “sodium detector,” or “sodium meter.”

The term “conductive species” refers to a material's ability to conductan electric current. Electrolytes are an example of a conductive speciesin dialysate fluids, such as, but not limited to the presence sodium,potassium, magnesium, phosphate, and chloride ions. A fluid's ability toconduct an electrical current is due in large part to the ions presentin the solution. A fluid's ability to conduct an electrical current isdue in large part to the ions present in the solution.

The terms “conduit”, “circuit”, and “flow path” refer to a vessel orpassageway having a void volume through which a fluid can travel ormove. A conduit can have a dimension parallel to the direction of travelof the fluid that is significantly longer than a dimension orthogonal tothe direction of travel of the fluid.

The term “connectable” refers to being able to be joined together forpurposes including but not limited to maintaining a position, allowing aflow of fluid, performing a measurement, transmitting power, andtransmitting electrical signals. The term “connectable” can refer tobeing able to be joined together temporarily or permanently.

The term “consisting of” includes and is limited to whatever follows thephrase “consisting of.” Thus, the phrase indicates that the limitedelements are required or mandatory and that no other elements may bepresent.

The term “consisting essentially of” includes whatever follows the term“consisting essentially of” and additional elements, structures, acts orfeatures that do not affect the basic operation of the apparatus,structure or method described.

The term “consumables” refers to components that are dissipated, wasted,spent or used up during the performance of any function in the presentinvention. Examples include a quantity of sodium, bicarbonate,electrolytes, infusates, sorbents, cleaning and disinfectingingredients, anticoagulants, and components for one or more concentratesolutions.

The terms “consumables cartridge” and “consumables container” refer toan object or apparatus having or holding one or more materials that aredepleted during operation of the system. The one or more materials maybe in solid and/or solution form and can be in separate compartments ofthe object or apparatus. The object or apparatus may be single use, ormay be replenished and used multiple times, for example, by refillingthe object to replace the consumed material.

The terms “contact”, “contacted”, and “contacting” refers, in context,to (1) a coming together or touching of objects, fluids, or surfaces;(2) the state or condition of touching or of immediate proximity; (3)connection or interaction. For example, in reference to a “dialysatecontacting a sorbent material” refers to dialysate that has cometogether, has touched, or is in immediate proximity to connect orinteract with any material or material layer of a sorbent container,system or cartridge.

The term “container” as used herein is a receptacle that may be flexibleor in-flexible for holding fluid or solid, such as for example a spentdialysate fluid, or a sodium chloride or sodium bicarbonate solution orsolid, or the like.

The term “contaminant” refers to an undesirable or unwanted substance ororganism that may cause impairment of the health of a subject receivinga treatment or of the operation of the system.

The term “control pump,” such as for example an “ultrafiltrate pump,”refers to a pump that is operable to pump fluid bi-directionally toactively control the transfer of fluid volume into or out of acompartment or circuit.

The terms “control reservoir,” “ultrafiltrate reservoir,” “solutionreservoir,” “therapy solution reservoir,” and “waste reservoir”, as thecase may be, refers, in context, to a vessel or container, optionallyaccessible by a control pump that contains a variable amount of fluid,including fluid that can be referred to as an ultrafiltrate. Thesereservoirs can function as a common reservoir to store fluid volume frommultiple sources in a system. Other fluids that can be contained bythese reservoirs include, for example, water, priming fluids, wastefluids, dialysate, including spent dialysate, and mixtures thereof. Incertain embodiments, the reservoirs can be substantially inflexible, ornon-flexible. In other embodiments, the reservoirs can be flexiblecontainers such as a polymer bag.

The term “control signals” refers to energy that is provided from oneelement of a system to another element of a system to convey informationfrom one element to another or to cause an action. For example, acontrol signal can energize a valve actuator to cause a valve to open orclose. In another example a switch on a valve can convey the open orclose state of a valve to a controller.

A “control system” consists of combinations of components that acttogether to maintain a system to a desired set of performancespecifications. The control system can use processors, memory andcomputer components configured to interoperate to maintain the desiredperformance specifications. It can also include fluid controlcomponents, and solute control components as known within the art tomaintain the performance specifications.

The terms “control valve” and “valve” refer to a device that can beoperated to regulate the flow of fluid through a conduit or flow path byselectively permitting fluid flow, preventing fluid flow, modifying therate of fluid flow, or selectively guiding a fluid flow to pass from oneconduit or flow path to one or more other conduits or flow paths.

The terms “controlled compliant flow path”, “controlled compliantdialysate flow path” and “controlled compliant solution flow path” referto flow paths operating within a controlled compliant system having thecharacteristic of controlled compliance, or of being controlledcompliant as defined herein.

A “controller,” “control unit,” “processor,” or “microprocessor” is adevice which monitors and affects the operational conditions of a givensystem. The operational conditions are typically referred to as outputvariables of the system wherein the output variables can be affected byadjusting certain input variables.

The terms “controlled compliance” and “controlled compliant” describethe ability to actively control the transfer of fluid volume into or outof a compartment, flow path or circuit. In certain embodiments, thevariable volume of fluid in a dialysate circuit or controlled compliantflow path expands and contracts via the control of one or more pumps inconjunction with one or more reservoirs. The volume of fluid in thesystem is generally constant (unless additional fluids are added to areservoir from outside of the system) once the system is in operation ifthe patient fluid volume(s), flow paths, and reservoirs are consideredpart of the total volume of the system (each individual volume maysometimes be referred to as a fluid compartment). The attachedreservoirs allow the system to adjust the patient fluid volume bywithdrawing fluid and storing the desired amount in an attached controlreservoir and/or by providing purified and/or rebalanced fluids to thepatient and optionally removing waste products. The terms “controlledcompliance” and “controlled compliant” are not to be confused with theterm “non-compliant volume,” which simply refers to a vessel, conduit,container, flow path, conditioning flow path or cartridge that resiststhe introduction of a volume of fluid after air has been removed from adefined space such as a vessel, conduit, container, flow path,conditioning flow path or cartridge. In one embodiment, and as discussedherein and shown in the drawings is that the controlled compliant systemcan move fluids bi-directionally. In certain cases, the bi-directionalfluid movement is across a semi-permeable membrane either inside oroutside a dialyzer. The bi-directional fluid flow can also occur across,through, or between vessels, conduits, containers, flow paths,conditioning flow paths or cartridges of the invention in selected modesof operation. The term “moving fluid bi-directionally” as used inconnection with a barrier, such as a semi-permeable membrane, refers tothe ability to move a fluid across the barrier in either direction.“Moving fluid bi-directionally” also can apply to the ability to movefluid in both directions in the flow path or between a flow path andreservoir in a controlled compliant system.

The terms “controlled compliant flow path”, “controlled compliantdialysate flow path” and “controlled compliant solution flow path” referto flow paths operating within a controlled compliant system having thecharacteristic of controlled compliance, or of being controlledcompliant as defined herein.

The term “convective clearance” refers to the movement of solutemolecules or ions across a semi-permeable barrier due to force createdby solvent molecules moving across the semi-permeable barrier.

The terms “controller,” “control unit,” “processor,” and“microprocessor” refers, in context, to a device which monitors andaffects the operational conditions of a given system. The operationalconditions are typically referred to as output variables of the systemwherein the output variables can be affected by adjusting certain inputvariables.

The terms “coordinately operates” and “coordinately operating” refer tocontrolling the function of two or more elements or devices so that thecombined functioning of the two or more elements or devices accomplishesa desired result. The term does not exclusively imply that all suchelements or devices are simultaneously energized.

The term “deaeration” refers to removing some or all of the aircontained in a liquid including both dissolved and non-dissolved aircontained in the liquid.

The terms “de-aeration flow path” and “de-aeration flow path” refer to aset of elements that are configured in fluid communication along a fluidflow pathway such that a liquid can be passed through the fluid flowpathway to accomplish removal of some or all of the air or gas containedin the liquid, including removal of air or gas that is dissolved in theliquid.

The terms “degas module” and “degassing module” refer to a componentthat separates and removes any portion of one or more dissolved orundissolved gas from a liquid. A degas module can include a hydrophobicmembrane for allowing ingress or egress of gases through a surface ofthe module while preventing the passage of liquid through that surfaceof the module.

The term “deionization resin” refers to any type of resin or materialthat can exchange one type of ion for another. In one specific case, theterm can refer to the removal of ions such as potassium, magnesium,sodium and calcium in exchange for hydrogen and/or hydroxide ions.

The term “detachable” refers to a characteristic of an object orapparatus that permits it to be removed and/or disconnected from anotherobject or apparatus.

The term “dialysate” describes a fluid into or out of which solutes froma fluid to be dialyzed diffuse through a membrane. A dialysate typicallycontains electrolytes that are close in concentration to thephysiological concentration of electrolytes found in blood. A commonsodium level for dialysate is approximately 140 mEq/L. Normal bloodsodium levels range from approximately 135 mEq/L to 145 mEq/L. The REDYsystem typically uses dialysate ranging from 120 mEq/L to 160 mEq/L. Incertain embodiment, a “predetermined limit” or “predeterminedconcentration” of sodium values can be based off the common sodiumlevels for dialysate and normal blood sodium levels. “Normal” saline at0/9% by weight and commonly used for priming dialyzers andextracorporeal circuits is 154 mEq/L.

The terms “dialysate flow loop”, “dialysate flow path”, and “dialysateconduit flow path” refers, in context, to a fluid pathway that conveys adialysate and is configured to form at least part of a fluid circuit forhemodialysis, hemofiltration, hemodiafiltration or ultrafiltration.

The terms “dialysate regeneration unit” and “dialysate regenerationsystem” refer to a system for removing certain electrolytes and wastespecies including urea from a dialysate after contact with a dialyzer.In certain instances, the component contained within the “dialysateregeneration unit” or “dialysate regeneration system” can decrease theconcentration or conductivity of at least one ionic species, or releaseand/or absorb at least one solute from a dialysate.

“Dialysis” is a type of filtration, or a process of selective diffusionthrough a membrane. Dialysis removes solutes of a specific range ofmolecular weights via diffusion through a membrane from a fluid to bedialyzed into a dialysate. During dialysis, a fluid to be dialyzed ispassed over a filter membrane, while dialysate is passed over the otherside of that membrane. Dissolved solutes are transported across thefilter membrane by diffusion between the fluids. The dialysate is usedto remove solutes from the fluid to be dialyzed. The dialysate can alsoprovide enrichment to the other fluid.

The terms “dialysis membrane,” “hemodialysis membrane,” “hemofiltrationmembrane,” “hemodiafiltration membrane,” “ultrafiltration membrane,” andgenerally “membrane,” refer, in context, to a semi-permeable barrierselective to allow diffusion and convection of solutes of a specificrange of molecular weights through the barrier that separates blood anddialysate, or blood and filtrate, while allowing diffusive and/orconvective transfer between the blood on one side of the membrane andthe dialysate or filtrate circuit on the other side of the membrane.

The term “dialyzer” refers to a cartridge or container with two flowpaths separated by semi-permeable membranes. One flow path is for bloodand one flow path is for dialysate. The membranes can be in the form ofhollow fibers, flat sheets, or spiral wound or other conventional formsknown to those of skill in the art. Membranes can be selected from thefollowing materials of polysulfone, polyethersulfone, poly(methylmethacrylate), modified cellulose, or other materials known to thoseskilled in the art.

“Diffusive permeability” is a property of a membrane describingpermeation by diffusion. Diffusion is the process of solutes moving froman area of higher concentration to an area of lower concentration.

The terms “diluate flow channel,” “feed stream,” “diluate stream,” andthe like, refer, in context, to a fluid line of solution entering anelectrodialysis cell or electrodialysis unit wherein the ionconcentration in the fluid solution is changed.

The terms “diluent” and “diluate” refer to a fluid having aconcentration of a specific species less than a fluid to which thediluent is added.

A “disc electrode” consists of an electrode with an electrode head inthe shape of a disc. A “rod electrode” refers to an electrode in theshape of a rod or cylinder, with one end functioning as an electrodehead. A “sheet electrode” refers to an electrode with an electrode headin the shape of a sheet. The sheet can be square, rectangular, circularor other solid planar geometries. A “mesh electrode” refers to anelectrode with an electrode head consisting of a mesh, where a mesh isthe same as that described for a mesh electrode. An “antenna electrode”refers to an electrode with an electrode head in the shape of anantenna, where antenna shape refers to a serpentine structure ofconductive wires or strips. A “pin electrode refers” to a rod electrodewith a small diameter. Other electrode and electrode head geometries canbe considered.

The term “disinfection fluid” refers to a solution for use in cleaningand disinfecting an apparatus for hemodialysis, hemodiafiltration orhemofiltration. The disinfection fluid may act thermally, chemically,and combinations thereof to inhibit growth of or to destroymicroorganisms. The “disinfection fluid” may further act to remove, atleast in part, a buildup of microorganisms on a surface of a fluid flowpath, such buildups of microorganisms may be commonly referred to as abiofilm.

The terms “diverted sample stream” and “diverting a sample stream” referredirecting part of a fluid from the main flow path to accomplishanother purpose, such as to measure a fluid characteristic, remove aportion of the fluid stream in order to take a sample. More that onesample stream may be diverted, such as a “first sample stream, “secondsample stream”, “third sample stream”, “fourth sample stream”, and thelike.

The term “dry” as applied to a solid or a powder contained in acartridge means not visibly wet, and may refer interchangeably toanhydrous and also to partially hydrated forms of those materials, forexample, monohydrates and dihydrates.

The term “downstream” refers to a direction in which a moving dialysateor other fluid moves within a conduit or flow path.

The term “downstream conductivity” refers to the conductivity of a fluidsolution as measured at a location of a fluid flow path in the directionof the normal fluid flow from a reference point.

The term “drain connection” refers to being joined in fluidcommunication with a conduit or vessel that can accept fluid egress fromthe system.

The term “dry composition” refers to a compound that does not contain asubstantial quantity of water and can include anhydrous forms as well ashydrates for example, monohydrates and dihydrates.

The term “effluent dialysate,” as used herein describes the discharge oroutflow after the dialysate has been used for dialysis.

The term “electrode” as used herein describes an electrical conductorused to make contact with a part of a fluid, a solid or solution. Forexample, electrical conductors can be used as electrodes to contact anyfluid (e.g. dialysate) to measure the conductivity of the fluid ordeliver or receive charge to the fluid. A “disc electrode” consists ofan electrode with an electrode head in the shape of a disc. A “rodelectrode” refers to an electrode in the shape of a rod or cylinder,with one end functioning as an electrode head. A “sheet electrode”refers to an electrode with an electrode head in the shape of a sheet.The sheet can be square, rectangular, circular or other solid planargeometries. A “mesh electrode” refers to an electrode with an electrodehead consisting of a mesh, where a mesh is the same as that describedfor a mesh electrode. An “antenna electrode” refers to an electrode withan electrode head in the shape of an antenna, where antenna shape refersto a serpentine structure of conductive wires or strips. A “pinelectrode” refers to a rod electrode with a small diameter. Otherelectrode and electrode head geometries can be considered.

The term “electrode array” refers to an array of one or more electrodescontained in an insulator substrate. The insulator substrate can berigid or flexible and acts to isolate the electrodes from each other. Anon-limiting example of an “electrode array” is a flex-circuit, which isa flexible circuit board containing electrodes.

The term “electrode head” refers to the portion of an electrode that isin physical contact with a fluid, that conductivity is to be measuredfrom.

The terms “electrode rinse” and “electrode rinse solution” refer to anysuitable solution such as sodium sulfate solution that preventsundesirable oxidation and flushes reactants from an electrode surface.

The terms “electrode rinse flow channel,” “electrode rinse stream,” andthe like refer to a fluid line of an electrode rinse or “electrode rinsesolution.”

The term “electrode rinse reservoir” refers to a vessel or container forholding the electrode rinse or electrode rinse solution. The reservoirmay have an inflexible or flexible volume capacity.

The term “electrodialysis” refers to an electrically driven membraneseparation process capable of separating, purifying, and concentratingdesired ions from aqueous solutions or solvents.

The term “electrodialysis cell” refers to an apparatus havingalternating anion- and cation-exchange membranes that can performelectrodialysis using an electrical driving force between an anode andcathode housed at opposite ends of the cell. The cell consists of adiluate compartment fed by a diluate stream and a concentratecompartment fed by a concentrate stream. One or more electrodialysiscells can be multiply arranged to form an “electrodialysis stack.”

The term “electrolyte” refers to an ion or ions dissolved in an aqueousmedium, including but not limited to sodium, potassium, calcium,magnesium, acetate, bicarbonate, and chloride.

The terms “electrolyte source” and “electrolyte source” refer to astored substance that provides one or more electrolytes.

The terms “equilibrated,” “equilibrate,” “to equilibrate,” and the like,refer to a state where a concentration of a solute in a first fluid hasbecome approximately equal to the concentration of that solute in thesecond fluid. However, the term equilibrated as used herein does notimply that the concentration of the solute in the first fluid and thesecond fluid have become equal. The term can also be used in referenceto the process of one or more gases coming into equilibrium where thegases have equal pressures or between a liquid and a gas.

The term “equilibrated to the solute species concentration” refers tomore specifically where a concentration of a particular solute speciesin a first fluid has become approximately equal to the concentration ofthat solute species in the second fluid. The concentration need not beexact.

The terms “evacuation volume”, “priming volume” and “void volume” referto the internal volume of a component or collection of componentscomprising a fluid flow path and are the volume of fluid that can beremoved from the fluid flow path to empty the fluid flow path if it hasbeen filled with fluid.

The term “extracorporeal,” as used herein generally means situated oroccurring outside the body.

The term “extracorporeal circuit” refers to a fluid pathwayincorporating one or more components such as, but not limited to,conduits, valves, pumps, fluid connection ports or sensing devicesconfigured therein such that the pathway conveys blood from a subject toan apparatus for hemodialysis, hemofiltration, hemodiafiltration orultrafiltration and back to the subject.

The terms “extracorporeal flow path pump” and “blood pump” refer to adevice to move or convey fluid through an extracorporeal circuit. Thepump may be of any type suitable for pumping blood, including thoseknown to persons of skill in the art, for example peristaltic pumps,tubing pumps, diaphragm pumps, centrifugal pumps, and shuttle pumps.

The term “feed solution” refers to a dialysate or ultrafiltrate fluidsolution introduced into part of the dialysis or ultrafiltrate system.For example a “feed solution” can refer to a dialysate or ultrafiltratefluid solution introduced to an electrodialysis cell.

The term “filtering media” refers to a material that can allow a fluidto pass through, but which inhibits passage of non-fluid substances thatare larger than a predetermined size.

The terms “filtrate regeneration unit” and “filtrate regenerationsystem” refer to a system for removing certain electrolytes and wastespecies including urea from a filtrate produced using filtration.

The terms “filtrate regeneration circuit”, “filtrate regeneration loop”,and the like, refer to a flow path containing fluid resulting fromfiltration; for the removal of certain electrolytes and waste speciesincluding urea.

The term “filtration” refers to a process of separating solutes from afluid, by passing the fluid through a filter medium across which certainsolutes or suspensions cannot pass. Filtration is driven by the pressuredifference across the membrane.

The term “first terminal end” of a flow path refers to one end of theflow path and “second terminal end” refers to another end of the flowpath. Neither the “first terminal end” nor the “second terminal end” hasany limitation on placement on an arterial or venous side.

The term “first terminal valve” refers to a valve substantially locatedat one end of a first fluid conduit without any requirement that thevalve be place on an arterial or venous side. Similarly, the term“second terminal valve” refers to a valve substantially located at oneend of a second fluid conduit and so on without any limitation onplacement on an arterial or venous side.

The term “flow loop” refers to a grouping of components that may guidethe movement of a fluid, convey the fluid, exchange energy with thefluid, modify the composition of the fluid, measure a characteristic ofthe fluid and/or detect the fluid. A flow loop comprises a route or acollection of routes for a fluid to move within. Within a flow loopthere may be more than one route that a volume of fluid can follow tomove from one position to another position. A fluid volume may movethrough a flow loop such that it recirculates, or passes the sameposition more than once as it moves through a flow loop. A flow loop mayoperate to cause fluid volume ingress to and fluid volume egress fromthe flow loop. The term “flow loop” and “flow path” often may be usedinterchangeably.

The term “flow path” refers to a route or a collection of routes for afluid to move within. Within a flow path there may be more than oneroute that a fluid can follow to move from a first position to a secondposition. A fluid may move through a flow path such that itrecirculates, or passes the same position more than once as it movesthrough a flow path. A flow path may be a single element such as a tube,or a flow path may be a grouping of components of any type that guidethe movement of a fluid. The term “flow loop” and “flow path” often maybe used interchangeably. Further types of flow paths may be furtherdefined; for example, (1) a recirculation flow path, would be a flowpath whose function is in whole or part is to recirculate fluid throughthe defined flow path; (2) a dialyzer recirculation flow path would be aflow path whose function is in whole or part is to recirculate fluidthrough the defined flow path having a dialyzer' (3) a controlledcompliant flow path would be a flow path would be a flow path that iscontrolled compliant as defined herein. Any of the defined flow pathsmay be referred to numerically, as a first flow path, second, third flowpath, or fourth flow path, and the like flow paths.

The terms “flow restriction”, “flow restriction device” and “flowrestrictor” refer to an element or grouping of elements that resist theflow of fluid through the element or grouping of elements such that thefluid pressure within a flow stream that passes through the element orgrouping of elements is greater upstream of the element or grouping ofelements than downstream of the element or grouping of elements. A flowrestrictor may be an active or passive device. Non-limiting examples ofpassive flow restriction devices are orifices, venturis, a narrowing, ora simple length of tubing with flow cross section that produces thedesired pressure drop when the fluid flows through it, such tubing beingessentially rigid or compliant. Non-limiting examples of active flowrestrictors are pinch valves, gate valves and variable orifice valves.

The term “flow stream” refers to fluid moving along a flow path

The term “fluid balance control pump” refers to where a control pump isused to adjust the concentration or amount of a solute or fluid in thesystem. For example, a fluid balance control pump is used forselectively metering in or selectively metering out a designated fluidwherein the concentration or amount of a solute or fluid is adjusted.

The term “fluid characteristic” refers to any chemical or biologicalcomponents that make up or can be found dissolved or suspended in thefluid or gas properties associated with the fluid; or to any physicalproperty of the fluid including, but not limited to temperature,pressure, general or specific conductivities associated with the fluidor related gases.

The term “fluid communication” refers to the ability of fluid to movefrom one component or compartment to another within a system or thestate of being connected, such that fluid can move by pressuredifferences from one portion that is connected to another portion.

The term “fluid port” refers to an aperture through which a liquid orgas can be conveyed.

The term “fluid port cap or plug” refers to a device that can beconnected to a fluid port to prevent fluid from passing through thefluid port. A fluid cap or plug may be configured into an apparatushaving multiple caps or plugs to prevent fluid from passing throughmultiple fluid ports when the apparatus is connected to the multiplefluid ports.

The term “flush reservoir” is used to describe a container that canaccept or store fluid that is removed from the system during rinsing orcleaning of fluid pathways of the system, including draining the systemafter cleaning and/or disinfection has been completed.

The term “forward osmosis” refers to a filtration method using anosmotic pressure gradient wherein a permeate side of a membrane containsa “draw” solution which has a higher osmotic potential than a feedsolution on the other side of the membrane. That higher osmoticpotential in the “draw” solution drives the filtration process whereinfluid moves through the membrane and is filtered in the process todilute the higher solute concentration fluid on the permeate side.

The term “gas port” refers to an aperture through which any gaseous formof matter can be conveyed.

“Gas phase pressure”, also known as “vapor”, is the equilibrium pressurefrom a liquid or a solid at a specific temperature. If the vapor is incontact with a liquid or solid phase, the two phases will be in a stateof equilibrium.

“Hemodiafiltration” is a therapy that combines hemofiltration andhemodialysis.

“Hemofiltration” is a therapy in which blood is filtered across asemi-permeable membrane. Water and solutes are removed from the bloodvia pressure-driven convection across the membrane. The sievingproperties of the membrane exclude certain solutes above a certainthreshold from crossing the membrane. One common sieving property is“albumin sieving.” In most situations it is not desirable to removealbumin during renal replacement therapy, as lower blood serum albuminis associated with increased mortality rates. In hemofiltration, solutessmall enough to pass through the membrane in proportion to their plasmaconcentration are removed. The driving force is a pressure gradientrather than a concentration gradient. A positive hydrostatic pressuredrives water and solutes across the filter membrane from the bloodcompartment to the filtrate compartment, from which it is drained.Solutes, both small and large, get dragged through the membrane at asimilar rate by the flow of water that has been engineered by thehydrostatic pressure. Hence, convection overcomes the reduced removalrate of larger solutes (due to their slow speed of diffusion) observedin hemodialysis. The rate of solute removal is proportional to theamount of fluid removed from the blood circuit, which can be adjusted tomeet the needs of a clinical situation. In general, the removal of largeamounts of plasma water from the patient requires volume substitution.Substitution fluid, typically a buffered solution close to the plasmawater composition a patient needs, can be administered pre or postfilter (pre-dilution mode, post-dilution mode).

“Hemodialysis” is a technique where blood and a “cleansing fluid” calleddialysate are exposed to each other separated by a semi-permeablemembrane. Solutes within the permeability range of the membrane passwhile diffusing along existing concentration gradients. Water andsolutes are also transferred by convection across a pressure gradientthat may exist across the dialysis membrane. The dialysate employedduring hemodialysis has soluble ions such as sodium, calcium andpotassium ions and is not pure water. The sieving properties of themembrane exclude certain solutes above a certain threshold from crossingthe membrane. One common sieving property is “albumin sieving.” In mostsituations it is not desirable to remove albumin during renalreplacement therapy, as lower blood serum albumin is associated withincreased mortality rates.

The term “hemofilter” refers to a apparatus (or may refer to a filter)used in hemofiltration. A hemofilter apparatus can be connected to anextracorporeal circuit and configured to operate with a semipermeablemembrane that separates at least a portion of the fluid volume fromblood to produce a filtrate fluid.

The term “horizontal to a central axis” refers to a relative position ofcomponents such as sensors that can be placed in a plane having portionsgenerally horizontal to the central axis.

The term “hydrophobic membrane” refers to a semipermeable porousmaterial that may allow gas phases of matter to pass through, but whichsubstantially resists the flow of water through the material due to thesurface interaction between the water and the hydrophobic material.

The terms “hydrophobic vent” and “hydrophobic vent membrane” refer to aporous material layer or covering that can resist the passage of aliquid such as water through the pores while allowing the passage of agas. The pores may also be of a sufficiently small size to substantiallyprevent the passage of microorganisms.

“Hemodiafiltration” is a therapy that combines hemofiltration andhemodialysis.

The term “perpendicular to a central axis” refers to the position ofcomponents, e.g. sensors that can be placed in a plane having portionsgenerally perpendicular to the central axis.

The term “in contact” as referred to herein denotes (a) a comingtogether or touching, as of objects or surfaces; or (b) the state orcondition of touching or of being in immediate proximity. “In contact”also includes fluids that are “in fluid communication with” with asolid, such as for example, a fluid, like a dialysate, in contact with amaterial layer of a sorbent cartridge, or a fluid in contact with asensor.

The term “impedance meter” refers to a device for measuring theopposition of an object or structure to an alternating current.

The term “impurity species” refers to solutes in the blood that are intoo high of a concentration in the blood from standard ranges known inthe art or that are solutes that have resulted from metabolism togenerate a non-healthy component now residing in the blood. An “impurityspecies” is one which is also regarded as a “waste species,” or “wasteproducts”.

The term “ion selective electrode” refers to electrodes coated with amaterial that only allows certain ions to pass through. An “ionselective electrode” (ISE), also known as a specific ion electrode(SIE), is a transducer (or sensor) that converts the activity of aspecific ion dissolved in a solution into an electrical potential, whichcan be measured by a voltmeter or pH meter. The voltage is theoreticallydependent on the logarithm of the ionic activity, according to theNernst equation. The sensing part of the electrode is usually made as anion-specific membrane, along with a reference electrode.

The terms “infusate container” and “infusate reservoir” refer to avessel, which can be substantially inflexible or non-flexible forholding a solution of one or more salts for the adjustment of thecomposition of a dialysate.

The term “infusate solution” refers to a solution of one or more saltsfor the adjustment of the composition of a dialysate, such as salts ofcalcium, magnesium, potassium, and glucose.

The term “infusate system” refers to a system that incorporates at leastone fluid pathway including components such as conduits, valves, pumpsor fluid connection ports, an infusate container or a controllerconfigured to add an infusate solution to the dialysate.

The term “interchangeable bicarbonate cartridge” refers to a bicarbonatecartridge that can be configured for removal and replacement with a likebicarbonate cartridge. Interchangeable bicarbonate cartridges can besingle use disposable, or re-fillable, re-usable containers.

The term “interchangeable sodium chloride cartridge” refers to a sodiumchloride cartridge that can be configured for removal and replacementwith a like sodium chloride cartridge. Interchangeable sodium chloridecartridges can be single use disposable, or re-fillable, re-usablecontainers.

The terms “introduce” and “introducing” refer to causing a substance tobecome present where it was not present, or to cause the amount orconcentration of a substance to be increased.

The term “ion-exchange material” refers to any type of resin or materialthat can exchange one type of ion for another. The “ion-exchangematerial” can include anion and cation exchange materials. In onespecific case, the term can refer to the removal of ions such aspotassium, magnesium, sodium, phosphate and calcium in exchange forother ions such as potassium, sodium, acetate, hydrogen and/orhydroxide.

An “ion-exchange resin” or “ion-exchange polymer” is an insoluble matrix(or support structure) that can be in the form of small (1-2 mmdiameter) beads, fabricated from an organic polymer substrate. Thematerial has a developed structure of pores on the surface of which aresites with easily trapped and released ions. The trapping of ions takesplace only with simultaneous releasing of other ions; thus the processis called ion-exchange. There are multiple different types ofion-exchange resin which are fabricated to selectively prefer one orseveral different types of ions. In one specific case, the term canrefer to the removal of ions such as potassium, magnesium, sodium,phosphate and calcium in exchange for other ions such as potassium,sodium, acetate, hydrogen and/or hydroxide.

The term “junction” refers to a common point of connection between twoor more flow paths or conduits that allows a liquid and/or a gas to movefrom one pathway or conduit to another. A junction may be a reversibleconnection that can be separated when transfer of a liquid and/or gasbetween the flow paths or conduits is not needed.

The term “kidney replacement therapy” as used herein describes the useof a provided system to replace, supplement, or augment the function ofa patient with impaired kidney function, such as would occur for apatient with Chronic Kidney Disease. Examples of kidney replacementtherapy would include dialysis, hemofiltration, hemodialysis,hemodiafiltration, peritoneal dialysis, and the like.

The terms “luer connector” and “luer adapter” refer to adapters orconnectors conforming to International Standards Organization (ISO)standards 594-2.

The term “manifold” refers to a collection of one or more fluid pathwaysthat are formed within a single unit or subassembly. Many types ofmanifolds can be used, e.g. a cleaning and/or disinfecting manifold isused to clean or disinfect the defined flow loop when the flow loop isconnected to the cleaning and/or disinfecting manifold.

The term “material layer” refers to the layers of materials found in asorbent cartridge. The material layers in a sorbent cartridge may haveone or more layers selected from a urease-containing material, alumina,zirconium phosphate, zirconium oxide, and activated carbon.

The term “memory” refers to a device for recording digital informationthat can be accessed by a microprocessor, such as RAM, Dynamic RAM,microprocessor cache, FLASH memory, or memory card.

The term “mesh electrode” refers to an electrode in the shape of a mesh,where a mesh consists of a planar structure with openings. The mesh canbe made from; overlapping wires or strips, a sheet machined ormanufactured to contain holes or openings, or a sheet with a permeable,porous structure. In all cases the mesh is manufactured from materialsthat result in electrodes, such as titanium, platinum, stainless steel,and iridium. In the case of an electrode mesh consisting of overlappingwires or strips, certain wires or strips can be isolated from otherwires or strips with an insulator material in order to apply onepolarity to certain wires or strips and the opposite polarity to otherwires or strips.

The term “metabolic waste species,” as used herein describes organic andinorganic components generated by a patient. They can be metabolicproducts such as urea, uric acid, creatinine, chlorides, inorganicsulfates and phosphate, or excess electrolytes such as sodium,potassium, etc. It will be understood that the specific “metabolic wastespecies” can vary between individuals depending on diet andenvironmental factors. Hence, the term is intended to encompass anywaste component that is normally removed by a kidney or by dialysiswithout restriction on the specific type of waste substance.

The term “mid-weight uremic wastes” refers to uremic wastes that canpass through a dialysis membrane and have a molecular weight less thanabout 66,000 g/mol and greater than about 1000 g/mol. An example of amiddle molecule is beta-2 microglobulin.

The term “mixing chamber” refers to a chamber or vessel, with one ormore inlet and outlet fluid streams, that provides mixing between thefluid streams entering the chamber.

The term “moving fluid bi-directionally” as used in connection with abarrier, such as a semi-permeable membrane, refers to the ability tomove a fluid across the barrier in either direction. “Moving fluidbi-directionally” also can apply to the ability to move fluid in bothdirections in the flow loop in a controlled compliant system.

A multiplexer” or “mux” is an electronic device that selects one ofseveral analog or digital input signals and forwards the selected inputinto a single line.

The term “nitrogenous waste” refers to any non-polymericnitrogen-containing organic compound originating from the blood of apatient. Nitrogenous waste includes urea and creatinine, which are both“waste species.”

The term “one-way valve” refers to a device that allows flow to pass inone direction through the valve, but prevents or substantially resistsflow through the valve in the opposite direction. Such devices caninclude devices commonly referred to as check valves

“Osmolarity” is defined as the number of osmoles of a solute per literof solution. Thus, a “hyperosmolar solution” represents a solution withan increase in osmolarity compared to physiologic solutions. Certaincompounds, such as mannitol, may have an effect on the osmoticproperties of a solution as described herein.

The term “parallel or wound hollow fiber assembly” refers to any devicethat incorporates a porous or non-porous hollow fiber material thatallows a gas to pass through the material wall of the hollow fibers, butresists the passage of a liquid through the material wall and isconfigured as multiple strands aligned in parallel or wrapped around acore. The liquid to be degassed may be conveyed through either theinside of the hollow fibers or around the outside of the hollow fibers.Optionally, a gas may be conveyed on the side of the material wall thatis opposite the liquid to be degassed. Optionally, a vacuum may beapplied on the side of the material wall that is opposite the liquid tobe degassed.

A “patient” or “subject” is a member of any animal species, preferably amammalian species, optionally a human. The subject can be an apparentlyhealthy individual, an individual suffering from a disease, or anindividual being treated for a disease.

The term “parallel to a central axis” refers to the position ofcomponents, e.g. sensors that can be placed in a plane having portionsgenerally parallel to the central axis.

The terms “pathway,” “conveyance pathway” and “flow path” refer to theroute through which a fluid, such as dialysate or blood travels.

The term “patient fluid balance” refers to the amount or volume of fluidadded to or removed from a subject undergoing a treatment.

The term “peristaltic pump” refers to a pump that operates bycompression of a flexible conduit or tube through which the fluid to bepumped passes.

The term “perpendicular to a central axis” refers to the position ofcomponents, e.g. sensors that can be placed in a plane having portionsgenerally perpendicular to the central axis.

“Peritoneal dialysis” is a therapy wherein a dialysate is infused intothe peritoneal cavity, which serves as a natural dialyzer. In general,waste components diffuse from a patient's bloodstream across aperitoneal membrane into the dialysis solution via a concentrationgradient. In general, excess fluid in the form of plasma water flowsfrom a patient's bloodstream across a peritoneal membrane into thedialysis solution via an osmotic gradient.

The term “pH-buffer modifying solution” refers to a solution that canreduce the acidity (pH) of the working dialysate solution when added tothe dialysate

The term “pH-buffer sensor” refers to a device for measuring the acidityor basicity (pH) and the buffer concentration of the dialysate solution.

The term “pH-buffer management system” refers to a system managing thepH and buffer concentration of a dialysate by adding, removing orgenerating a fluid to the dialysate such that the dialysate is modifiedby the pH-buffer management system to have a different pH and bufferconcentration.

The term “pH-buffer measurement system” refers to a system measuring thepH and/or buffer concentration of a dialysate or fluid within thesystem.

The terms “portable system” and “wearable system” refers to a system inwhole or in part having a mass and dimension to allow for transport by asingle individual by carrying the system or wearing the system on theindividual's body. The terms are to be interpreted broadly without anylimitation as to size, weight, length of time carried, comfort, ease ofuse, and specific use by any person whether man, woman or child. Theterm is to be used in a general sense wherein one of ordinary skill willunderstand that portability as contemplated by the invention encompassesa wide range of weights, geometries, configurations and size.

The term “potable water” refers to drinking water or water that isgenerally safe for human consumption with low risk of immediate or longterm harm. The level of safety for human consumption can depend on aparticular geography where water safe for human consumption may bedifferent from water considered safe in another jurisdiction. The termdoes not necessarily include water that is completely free ofimpurities, contaminants, pathogens or toxins. Other types of watersuitable for use in the present invention can include purified,deionized, distilled, bottled drinking water, or other pre-processedwater that would be understood by those of ordinary skill in the art asbeing suitable for use in dialysis.

The term “potassium-modified fluid” refers to fluid having a differentconductivity or potassium concentration compared to a second fluid towhich the potassium-modified fluid is added to modify the conductivityor potassium concentration of the second fluid.

The terms “physiologically compatible fluid” and “physiologicalcompatible solution” refer to a fluid that can be safely introduced intothe bloodstream of a living subject.

The term “plumbing,” as used herein generally describes any system ofvalves, conduits, channels, and lines for supplying any of the fluidsused in the invention.

The term “porosity,” as used herein describes the fraction of open porevolume of a membrane.

The terms “pressure differential” and “pressure drop” refer to thedifference in pressure measurements of a fluid between two points ofmeasurement.

The terms “pressure meter” and “pressure sensor” refer to a device formeasuring the pressure of a gas or liquid in a vessel or container.

The terms “priming process” and “priming” refer to the process ofconveying a liquid into the void volume of a fluid pathway to fill thepathway with liquid.

The term “priming volume” refers to the volume of priming fluid requiredto fill the void volume of the subject pathway, device, or component, asthe particular case may be.

The term “priming overflow reservoir” refers to a reservoir which duringpriming is used to collect the overflow of fluid during the primingprocess.

The terms “processor,” “computer processor,” and “microprocessor” asused herein are broad terms and are to be given their ordinary andcustomary meaning to a person of ordinary skill in the art. The termsrefer without limitation to a computer system, state machine, processor,or the like designed to perform arithmetic or logic operations usinglogic circuitry that responds to and processes the basic instructionsthat drive a computer. In some embodiments, the terms can include ROM(“read-only memory”) and/or RAM (“random-access memory”) associatedtherewith.

The term “programmable” as used herein refers to a device using computerhardware architecture with a stored program and being capable ofcarrying out a set of commands, automatically that can be changed orreplaced.

The term “pump” refers to any device that causes the movement of fluidsor gases by the application of suction or pressure.

The term “pulsatile pump” refers to a pump where the pumped fluidundergoes periodic variation in velocity and/or pressure.

The terms “pump rate” and “volumetric pumping rate” refer to the volumeof fluid that a pump conveys per unit of time.

The term “purified water” refers to water that has been physicallyprocessed to remove at least a portion of at least one impurity from thewater.

The term “outlet stream” refers to a fluid stream exiting a chamber,vessel or cartridge.

The terms “reconstitute” and “reconstituting” refer to creating asolution by addition of a liquid to a dry material or to a solution ofhigher concentration to change the concentration level of the solution.A “reconstitution system” in one use, is a system that rebalances thedialysate in the system to ensure it contains the appropriate amount ofelectrolytes and buffer.

The term “refilled” refers to having replenished or restored a substancethat has been consumed or degraded.

The terms “sorbent regeneration”, “sorbent regeneration system”,“sorbent system, and the like, refer, in context, to devices that arepart of a sorbent regenerated dialysate delivery system forhemodialysis, functioning as an artificial kidney system for thetreatment of patients with renal failure or toxemic conditions, and thatconsists of a sorbent cartridge and the means to circulate dialysatethrough this cartridge and the dialysate compartment of the dialyzer.The device is used with the extracorporeal blood system and the dialyzerof the hemodialysis system and accessories. The device may include themeans to maintain the temperature, conductivity, electrolyte balance,flow rate and pressure of the dialysate, and alarms to indicate abnormaldialysate conditions. The sorbent cartridge may include absorbent, ionexchange and catalytics.

The term “shunt,” as most often used herein describes a passage betweenchannels, in the described filtration and purification systems, whereinthe shunt diverts or permits flow from one pathway or region to another.An alternate meaning of “shunt” can refer to a pathway or passage bywhich a bodily fluid (such as blood) is diverted from one channel,circulatory path, or part to another. The term “bypass” can often beused interchangeably with the term “shunt.”

The term “sodium-concentrate solution” refers to a solution having ahigh concentration of sodium ions relative to another solution or fluid.

The terms “sodium chloride cartridge” and “sodium chloride container”refer to an object that can be a stand-alone enclosure or alternativelycan be integrally formed with an apparatus for hemodialysis,hemodiafiltration, or hemofiltration. The object can store a source ofsodium, such as sodium chloride in solid and/or solution form, and canbe configured to interface with at least one other functional modulefound in systems for hemodialysis, hemodiafiltration, or hemofiltration.For example, the sodium chloride cartridge or container can contain atleast one fluid pathway and include components such as conduits, valves,filters or fluid connection ports.

The term “regenerative capacity of the sorbent” refers to the remainingcapacity for the sorbent cartridge or a particular material layer of thesorbent cartridge to perform its intended function.

The term “regenerative substance” refers to a sorbent material containedin a “regeneration module.” The term “first chosen regenerativesubstance,” as used in the present invention refers to a particularregenerative substance, identified as “first chosen regenerativesubstance.” The term “second chosen regenerative substance” refers to aparticular regenerative substance, identified as “second chosenregenerative substance.”

The term “regeneration module” refers to an enclosure having one or moresorbent materials for removing specific solutes from solution, such asurea. In certain embodiments, the term “regeneration module” refers toone or more regeneration cartridge or regeneration unit. In certainembodiments, the term “regeneration module” includes configurationswhere at least some of the materials contained in the module do not actby mechanisms of adsorption or absorption.

The terms “remnant volume” and “residual volume” refer to the volume offluid remaining in a fluid flow path after the fluid flow path has beenpartially emptied or evacuated.

The terms “replacement fluid” and “substitution fluid” refer to fluidthat is delivered to the blood of a subject undergoing convective renalreplacement therapies such as hemofiltration or hemodiafiltration inorder to replace at least a portion of the fluid volume that is removedfrom the subject's blood when the blood is passed through a hemofilteror a dialyzer.

The term “reserve for bolus infusion” refers to an amount of solutionavailable, if needed, for the purpose of administering fluid to asubject receiving therapy, for example, to treat an episode ofintradialytic hypotension.

The term “reusable” refers to an item that is used more than once.Reusable does not imply infinitely durable. A reusable item may bereplaced or discarded after one or more use.

The term “reverse osmosis” refers to a filtration method of forcing asolvent from a region of high solute concentration through asemi-permeable membrane to a region of low solute concentration byapplying a pressure in excess of osmotic pressure. To be “selective,”this membrane should not allow large molecules or ions through the pores(holes), but should allow smaller components of the solution (such asthe solvent) to pass freely.

The term “reverse osmosis rejection fraction” refers to the resultingsolute that is retained on the pressurized side of the membrane and thepure solvent is allowed to pass to the other side in a reverse osmosissystem.

The term “reversible connections” refers to any type of detachable,permanent or non-permanent connection configured for multiple uses.

The term “salination pump” refers to a pump configured to move fluidand/or control movement of fluid through a conditioning flow path, suchas through or from a source of a conditioning material such as sodiumchloride or sodium bicarbonate.

The term “salination valve” refers to a valve configured to control theflow of fluid in a conditioning flow path, such as through or from asource of a conditioning material such as sodium chloride or sodiumbicarbonate.

The term “segment” refers to a portion of the whole, such as a portionof a fluid flow path or a portion of a fluid circuit. A segment is notlimited to a tube or conduit, and includes any grouping of elements thatare described for a particular segment. Use of the term “segment,” byitself, does not imply reversible or detachable connection to anothersegment. In any embodiment, a segment may be permanently connected toone or more other segments or removably or detachably connected to oneor more segments.

The terms “selectively meter fluid in” and “selectively meter fluid out”generally refer to a process for controllably transferring fluids fromone fluid compartment (e.g. a selected patient fluid volume, flow path,or reservoir) to another fluid compartment. One non-limiting example iswhere a control pump may transfer a defined fluid volume container,reservoirs, flow paths, conduit of the controlled compliant system. Whenfluid is moved from a reservoir into another part of the system, theprocess is referred to as “selectively metering fluid in” as related tothat part of the system. Similarly, one non-limiting example of removinga defined volume of dialysate from a dialysate flow path in a controlledcompliant system and storing the spent dialysate in a control reservoir,can be referred to as “selectively metering-out” the fluid from thedialysate flow path.

The terms “semi-permeable membrane”, “selectively permeable membrane”,“partially permeable membrane”, and “differentially permeable membrane”,refer to a membrane that will allow certain molecules or ions to passthrough it by diffusion and occasionally specialized “facilitateddiffusion”. The rate of passage depends on the pressure, concentration,and temperature of the molecules or solutes on either side, as well asthe permeability of the membrane to each solute. The term“semi-permeable membrane” can also refer to a material that inhibits thepassage of larger molecular weight components of a solution whileallowing passage of other components of a solution having a smallermolecular weight. For example, Dialyzer membranes come with differentpore sizes. Those with smaller pore size are called “low-flux” and thosewith larger pore sizes are called “high-flux.” Some larger molecules,such as beta-2-microglobulin, are not effectively removed with low-fluxdialyzers. Because beta-2-microglobulin is a large molecule, with amolecular weight of about 11,600 daltons, it does not pass effectivelythrough low-flux dialysis membranes.

The term “sensor,” which can also be referred to as a “detector” incertain instances, as used herein can be a converter that measures aphysical quantity of a matter in a solution, liquid or gas, and canconvert it into a signal which can be read by an electronic instrument.

The term “sensor element” refers to a device or component of a systemthat detects or measures a physical property.

The terms “sodium management system” and “sodium management” broadlyrefer to a system or process that can maintain the sodium ionconcentration of a fluid in a desired range. In certain instances, thedesired range can be within a physiologically-compatible range. Thesodium ion concentration of an input solution can be modified by anymeans including application of an electrical field.

The term “sodium-modified fluid” refers to fluid having a differentconductivity or sodium concentration compared to a second fluid to whichthe sodium-modified fluid is added to modify the conductivity or sodiumconcentration of the second fluid.

The term “sodium conduit flow path” refers to a flow path in fluidcommunication with a sodium chloride cartridge which then can pumpsaturated sodium solution into the dialysate by pumping and meteringaction of a salination pump.

The term “sodium source” refers to a source from which sodium can beobtained. For example, the sodium source can be a solution containingsodium chloride or a dry sodium chloride composition that is hydrated bythe system.

The term “solid potassium” refers to a solid composition containing asalt of potassium such as potassium chloride at any purity level. Ingeneral, the solid potassium will be easily soluble in water to form asolution.

The term “solid sodium” refers to a solid composition containing a saltof sodium such as sodium chloride at any purity level. In general, thesolid potassium will be easily soluble in water to form a solution andof high purity.

The term “solid bicarbonate” refers to a composition containing a saltof bicarbonate such as sodium bicarbonate at any purity level. Ingeneral, the solid bicarbonate will be easily soluble in water to form asolution.

The term “solute” refers to a substance dissolved, suspended, or presentin another substance, usually the component of a solution present in thelesser amount.

The terms “sorbent cartridge” and “sorbent container” refer to acartridge containing one or more sorbent materials for removing specificsolutes from solution, such as urea. The term “sorbent cartridge” doesnot necessarily require the contents in the cartridge be sorbent based.In this connection, the sorbent cartridge may include any suitableamount of one or more sorbent materials. In certain instances, the term“sorbent cartridge” refers to a regeneration cartridge which may includeone or more sorbent materials in addition to one or more otherregeneration materials. “Sorbent cartridge” includes configurationswhere at least some of the materials contained in the cartridge do notact by mechanisms of adsorption or absorption.

The term “source of cations” refers a source from which cations can beobtained. Examples of cations include, but are not limited to, calcium,magnesium and potassium. The source can be a solution containing cationsor a dry composition that is hydrated by the system. The cation infusatesource is not limited to cations and may optionally include othersubstances to be infused into a dialysate or replacement fluid.Non-limiting examples include glucose, dextrose, acetic acid and citricacid.

The term “specified gas membrane permeability” refers to a determinedrate at which a gas membrane will allow a gas to pass through themembrane from a first surface to a second surface, the rate beingproportional to the difference in absolute pressure of the gas inproximity to the first side of the membrane and in proximity to thesecond side of the membrane.

The term “spent dialysate” refers to a dialysate that has been contactedwith blood through a dialysis membrane and contains one or moreimpurity, or waste species, or waste substance, such as urea.

The term “static mixer” refers to a device that mixes two or morecomponent materials in a fluid solution without requiring the use ofmoving parts.

The term “substantially inflexible volume” refers to a three-dimensionalspace within a vessel or container that can accommodate a maximum amountof non-compressible fluid and resists the addition of any volume offluid above the maximum amount. The presence of a volume of fluid lessthan the maximum amount will fail to completely fill the vessel orcontainer. Once a substantially inflexible volume has been filled with afluid, removal of fluid from that volume will create a negative pressurethat resists fluid removal unless fluid is added and removedsimultaneously at substantially equal rates. Those skilled in the artwill recognize that a minimal amount of expansion or contraction of thevessel or container can occur in a substantially inflexible volume;however, the addition or subtraction of a significant volume of fluidover a maximum or minimum will be resisted.

The term “tap water” refers to water, as defined herein, from a pipedsupply.

The term “temperature sensor” refers to a device that detects ormeasures the degree or intensity of heat present in a substance, object,or fluid.

A “therapy solution reservoir” refers to any container or reservoir thatholds a physiological compatible fluid.

The term “total bicarbonate buffer concentration” refers to the totalconcentration of bicarbonate (HCO₃ ⁻) ion and a conjugate acid ofbicarbonate in a solution or composition.

A “therapy solution reservoir” refers to any container or reservoir thatholds a physiological compatible fluid.

The terms “treating” and “treatment” refer to the management and care ofa patient having a pathology or condition by administration of one ormore therapy contemplated by the present invention. Treating alsoincludes administering one or more methods of the present invention orusing any of the systems, devices or compositions of the presentinvention in the treatment of a patient. As used herein, “treatment” or“therapy” refers to both therapeutic treatment and prophylactic orpreventative measures. “Treating” or “treatment” does not requirecomplete alleviation of signs or symptoms, does not require a cure, andincludes protocols having only a marginal or incomplete effect on apatient.

The term “uremic wastes” refers to a milieu of substances found inpatients with end-stage renal disease, including urea, creatinine,beta-2-microglobulin.

The term “ultrafiltrate” refers to fluid that is removed from a subjectby convection through a permeable membrane during hemodialysis,hemofiltration, hemodiafiltration, or peritoneal dialysis. The term“ultrafiltrate,” as used herein, can also refer to the fluid in areservoir that collects fluid volume removed from the patient, but sucha reservoir may also include fluids or collections of fluids that do notoriginate from the subject.

The term “ultrafiltration” refers to subjecting a fluid to filtration,where the filtered material is very small; typically, the fluidcomprises colloidal, dissolved solutes or very fine solid materials, andthe filter is a microporous, nanoporous, or semi-permeable medium. Atypical medium is a membrane. During ultrafiltration, a “filtrate” or“ultrafiltrate” that passes through the filter medium is separated froma feed fluid. In general, when transport across a membrane ispredominantly diffusive as a result of a concentration driving force,the process is described herein as dialysis. When transport is primarilyconvective as a result of bulk flow across the membrane induced by apressure driving force, the process is ultrafiltration or hemofiltrationdepending on the need for substitution solution as the membrane passessmall solutes but rejects macromolecules. The term “ultrafiltration” canalso refer to the fluid removal from blood during a dialysis or ahemofiltration process. That is, ultrafiltration refers to the processof passing fluid through a selective membrane, such as a dialysis orhemofiltration membrane, in either a dialysis, a hemodiafiltration, or afiltration process.

The terms “unbuffered sodium bicarbonate” and “solution of unbufferedsodium bicarbonate” refer to a sodium bicarbonate composition that isnot buffered with a conjugate acid or base in any amount, proportion orpH adjusted.

The term “upstream” refers to a direction opposite to the direction oftravel of a moving dialysate or other fluid within a conduit or flowpath.

The term “Urea Reduction Ratio” or “URR” refers to a ratio defined bythe formula below:

${URR} = {\frac{U_{pre} - U_{post}}{U_{pre}} \times 100\%}$Where:U_(pre) is the pre-dialysis urea levelU_(post) is the post-dialysis urea levelWhereas the URR is formally defined as the urea reduction “ratio”, inpractice it is informally multiplied by 100% as shown in the formulaabove, and expressed as a percent.

The term “urea sensor” refers to a device for measuring or allowing forthe calculation of urea content of a solution. The “urea sensor” caninclude devices measuring urease breakdown of urea and measurement ofthe resulting ammonium concentration. The sensing methods can be basedon any one of conductimetric, potentiometric, thermometric,magnetoinductic, optical methods, combinations thereof and other methodsknown to those of skill in the art.

The term “vacuum” refers to an action that results from application of apressure that is less than atmospheric pressure, or negative to thereference fluid or gas.

The term “vent” as referred to in relationship to a gas, refers topermitting the escape of a gas from a defined portion of the system,such as, for example, as would be found in the degassing module.

The term “void volume” refers to a specific volume that can be occupiedby a fluid in a defined space such as a dialysate circuit of theinvention including all components contained therein.

The terms “waste species,” “waste products” and “impurity species”refers to any molecular or ionic species originating from the patient orsubject, including metabolic wastes, molecular or ionic speciesincluding nitrogen or sulfur atoms, mid-weight uremic wastes andnitrogenous waste. Waste species are kept within a specific homeostasisrange by individuals with a healthy renal system.

The term “waste fluid” refers to any fluid that does not have a presentuse in the operation of the system. Non-limiting examples of wastefluids include ultrafiltrate, or fluid volume that has been removed froma subject undergoing a treatment, and fluids that are drained or flushedfrom a reservoir, conduit or component of the system.

The term “water feed” refers to a source of water that is added to adialysate flow path by means of a pump or other delivery system.

The term “water source” refers to a source from which potable orunpotable water can be obtained.

The term “water source connection” or “water feed” refers to a state offluid communication that enables water to be obtained from a watersource and connected or feed into a receiving source or flow path.

The term “within” when used in reference to a sensor or electrodelocated “within” the sorbent cartridge refers to all, or part of thesensor or electrode is located inside, or encased by, at least part ofthe inner chamber formed from the sorbent cartridge wall.

The term “working dialysate solution” refers to a dialysate solutionthat is undergoing active circulation or movement through a systemincluding conduits, pathways, dialyzers and cartridges.

Measuring Dialysis

End stage renal disease (ESRD) results in a clinical condition calleduremia, a toxic state resulting from accumulation in blood and tissuesof solutes that are normally excreted by the kidneys. An importantfunction of hemodialysis is to treat uremia by blood purification thatremoves the toxic solutes directly from the blood and indirectly fromother tissues. Diffusive removal of small solutes across a semipermeablemembrane by concentration gradient between blood and dialysate is thetechnique responsible for much of the blood purification that occursduring hemodialysis. The proportion of accumulated toxins removed fromthe blood and tissue by hemodialysis therapy can be used to quantify thedialysis dose. There are many solutes that accumulate at different ratesin association with uremia. Medical science has not fully evaluated allof the solutes nor determined acceptable blood and tissue concentrationsfor each solute. Given this situation, clearance of a marker solute,urea, is commonly utilized to quantify the general dialysis dose given.Further, clearance of the marker solute, urea, has been correlated tomorbidity and mortality of ESRD patients being treated by dialysis

The principal waste species removed during treatment of a patient isurea that accumulates in the blood of individuals based on variousdegrees of kidney disease or impairment. Since urea is an electricallyneutral species, a dialysate regeneration unit can convert urea to acharged ammonium species that can then be removed from the circulatingdialysate within the dialysate flow loop. However, in order to maintainelectrical neutrality, the removal of charged ammonium species has to bematched by exchange with another charged species, which is sodium ion incertain embodiments. As such, the concentration of sodium ions canincrease over time through use of the sorbent materials and can bespecifically monitored by the conductivity monitoring system.

Loss of renal function also can result in loss of the ability to balancethe intake and elimination of calcium, magnesium, potassium andphosphorus that is necessary to maintain homeostasis within the tightrange necessary for health. Regulation of calcium and magnesium withinthese tight ranges is critical to physiologic function. Altered mineralmetabolism, including calcium and magnesium, contributes to bonedisease, cardiovascular disease, and other clinical problems in patientswith end-stage renal disease.

Disorders of mineral metabolism are independently associated withmortality and morbidity associated with cardiovascular disease andfracture in hemodialysis patients, and increased serum calciumconcentration is associated with increased risk of death in hemodialysispatients. Hypermagnesemia can be manifested by hypocalcaemia,hypotension, bradycardia, osteodystrophy and bone pain, impaired cardiaccontractility and intradialytic hemodynamic instability, atherosclerosisand vascular calcification, and has been demonstrated as a significantdeterminant, inversely correlated to serum parathyroid concentration,independent of calcium and phosphorus.

Calcium and magnesium exist in the blood in free ionized and boundforms, but it is the serum ionized form that is biologically active andintegrated into the body's regulatory systems that maintain homeostasis.Although ionized serum calcium is most important, total serum calcium istypically measured for hemodialysis patients, due to the lower cost andready availability of the test for total calcium, as opposed to serumionized calcium. Total serum calcium measurements do not assesshypocalcaemia and hypercalcaemia as accurately as ionized serum calciummeasurements and, further, methods to determine adjusted serum calciumare no more accurate than total serum calcium measurements in predictinghypo and hypercalcaemia. Further, while an individual's diet andmedications may cause calcium and magnesium levels to fluctuate daily,for reasons of cost and convenience, the blood tests are typicallyperformed only monthly.

The United States National Kidney Foundation Dialysis Outcome QualityInitiative (DOQI) has approved three measures for monitoring deliveredhemodialysis dose for thrice-weekly treatment: urea reduction ratio(URR), Kt/V by urea kinetic modeling (UKM), and Kt/V by the secondgeneration Daugirdas formula. Each measurement method utilizes, at aminimum, pre- and post-dialysis blood urea (BUN) measurements.

It will be understood by those of skill in the art that URR is arelatively simple method to quantify dialysis dose as proposed by Lowrieet al. (Lowrie E G, Lew N L. “The urea reduction ratio (URR): A simplemethod for evaluating hemodialysis treatment.” Contemp Dial Nephrol.1991; 12:11-20). URR is the ratio of urea removed to starting urea,calculated:

$\begin{matrix}{{URR} = \frac{\left( {{BUN}_{pre} - {BUN}_{post}} \right)}{{BUN}_{pre}}} & \left( {{Equation}1} \right)\end{matrix}$

-   -   where,    -   BUN_(pre)—blood urea concentration at start of dialysis session    -   BUN_(post)—blood urea concentration at end of dialysis session

Kt/V is a dimensionless expression of the fractional clearance of urea,where,

-   -   K—dialyzer clearance rate of urea (mL/min)    -   t—dialysis time (min)    -   V—volume of distribution of urea, approximately equal to        patient's total body water (mL)

It will be understood by those of skill in the art that Urea KineticModeling (UKM) is a complex, computer-based method of estimating ureaclearance developed by Gotch and Sargent to quantify dialysis dose basedon data from a National Cooperative Dialysis Study (Gotch F A, Sargent JA “A mechanistic analysis of the National Cooperative Dialysis Study(NCDS)”. Kidney int. 1985; 28:526-34). UKM includes factors forestimated dialyzer clearance, dialysis session time, and the patient'surea distribution volume, urea generation rate, pre and post-dialysisBUN, ultrafiltration volume, interdialytic weight gain, interdialyticinterval, and clearance by residual renal function. Urea distributionvolume is equal to the total volume in a patient where urea is present,and is approximately equal to the volume of water in a patient. Acomputer is used in UKM to iteratively solve two equations until thesolution converges.

A second generation Daugirdas formula calculates Kt/V from pre andpost-dialysis BUN, dialysis session time, ultrafiltration volume, andpost-dialysis weight (Daugirdas J T. “Second generation logarithmicestimates of single-pool variable volume Kt/V: and analysis of error.” JAm Soc Nephrol. 1993; 4:1205-13).

It will be appreciated by those of skill in the art that each of thethree methods approved by the United States National Kidney FoundationDialysis Outcome Quality Initiative (DOQI) for measuring deliveredhemodialysis dose require, at minimum, two measurement of the patient'sblood urea concentration.

Conductivity Monitor

The present invention provides for the determination of urea content(amount or concentration) in a spent dialysate in real-time fordetermination of adequacy or efficiency of dialysis therapy includingbut not limited to hemodialysis and hemodiafiltration, and alsoultrafiltration. In particular, the invention is directed toward aconductivity monitor that can operate with a dialysate regeneration unitto perform dialysis with a limited volume of dialysate. In anyembodiment, a working dialysate fluid can be circulated in a dialysisflow loop between a dialyzer and a dialysate regeneration unit, certainembodiments of which include a dialysate regeneration cartridge. Spentdialysate containing at least one waste species elutes from an outlet ofthe dialyzer during treatment where the spent dialysate is passedthrough the dialysate regeneration unit where waste species includingurea are removed from the dialysate. Using the dialysate regenerationunit, the working dialysate can be regenerated for recirculation throughthe dialyzer by the removal of waste species and the re-addition and/orre-constitution of species needed for a biocompatible dialysate, such asbuffers, calcium ions, potassium ions, magnesium ions and othercomponents typically employed for dialysate solutions. The conductivitymonitor operating with systems and methods can also provide inputs forthe monitoring of sodium ion concentration and/or conductivity of thedialysate and operate with a means to add a sodium-modified fluid orother infusates to the dialysate flow loop when needed to adjustconductivity or electrolyte concentration.

Blood circulating through a dialyzer via an extracorporeal circuitexchanges waste components with dialysate circulating through thedialyzer and dialysate flow loop. Waste species including ions anduremic toxins, such as uric acid, creatinine, and β2-microglobin, andurea diffuse from the blood to the dialysate within the dialyzer via asemipermeable membrane contained therein. As such, the limited volume ofdialysate within the dialysate flow loop can reach equilibrium with thecontent of waste species in the blood without ongoing removal of wastespecies from the dialysate to maintain a concentration gradient of wastespecies between the blood and the dialysate within the dialysate flowloop. During treatment employing the dialysate regeneration unit, theurea content of the spent dialysate will normally be less than theactual urea content of the blood due to on-going removal of urea fromthe dialysate as part of dialysate regeneration. The urea concentrationdifference between the blood and the dialysate depends on severalfactors (e.g. point in treatment, flow rates, dialyzer efficiency, etc.)such that urea content of the blood cannot be readily determined solelythrough measurement of real-time concentration of urea in the dialysate.

The sensing components, systems and methods of the invention can providereal-time information regarding cleared solutes within the dialysatestream that can be applied to detect and measure these factors so thatcorrective action can be taken within the dialysis session or betweendialysis sessions to ensure that the dialysis session clearance goalsare met. Dialysis standards of care are used to establish specificsession clearance goals (Kt/V) that are to be achieved by hemodialysistreatment. The invention can also demonstrate and document that aprescribed clearance, Kt/V, has been achieved by the dialysis therapyprovided. The present invention can also provide for urea Kt to bemeasured directly such that clearance is documented in the medicalrecord. Similarly, measurements of urea reduction ratio (URR) andequilibrated Kt/V (eKt/V) are also documented.

Many factors can compromise the effective clearance achieved during adialysis session such that clearance, Kt/V, differs from what would bepredicted by the configuration of the dialyzer, dialysis and blood flowrates, etc. Factors include blood access recirculation, accessconnection errors, dialyzer clotting, blood flow errors, dialysissession interruptions, and dialyzer variability. However, in anyembodiment, the sensing methods of the present invention can providereal-time information regarding cleared solutes within the dialysatestream that can be applied to detect and measure these factors so thatcorrective action can be taken within the dialysis session or betweendialysis sessions to ensure that the dialysis session clearance goalsare met.

In any embodiment, a dialysate regeneration cartridge, such as a sorbentcartridge, can contain several materials and/or sorbents that arecapable of removing solutes from the dialysate including: urea,phosphate, calcium, magnesium, potassium, creatinine, uric acid,beta-2-microglobulin and sulfate. The regeneration cartridge can alsocontain components or materials that release or bind sodium during theprocess of removing solutes from the dialysate. For example, thedialysate regeneration cartridge can be a sorbent cartridge containingactivated carbon, urease, zirconium phosphate and hydrous zirconiumoxides. In particular, a urease-containing material can convert neutralurea to an ammonium salt that affects the conductivity of the dialysateand allows for ammonium, and hence nitrogen, to be removed by cationexchange with other sorbent materials. In certain embodiments, theurease-material and sorbent materials can be contained in a singlehousing. In other embodiments, the urease-material and sorbent materialscan be contained in multiple housings including two or more housings.

In some embodiments, a conductivity monitoring system is provided formeasuring the conductivity change in the dialysate affected by specificsorbent and/or urease-containing materials individually or incombination. For example, the conductivity monitoring system can measurethe change in conductivity of spent dialysate prior to contact with theurease-containing material and after completing contact with theurease-containing materials. As such, the change in conductivity causedby the conversion of urea to ammonium salts can be determined prior todownstream contact with other materials that may further affectconductivity. In other embodiments, the conductivity monitoring systemcan measure the change in conductivity affected by non-urease containingmaterials to evaluate the effectiveness and performance of sorbentmaterials.

Regeneration of the dialysate within the dialysate flow loop can beachieved through contacting the dialysate with sorbents contained withinthe dialysate generation unit. Examples of useful sorbent materialsinclude the REDY sorbent system and U.S. Pat. Nos. 3,669,880; 3,989,622;4,581,141; 4,460,555; 4,650,587; 3,850,835; 6,627,164; 6,818,196; and7,566,432 and U.S. Patent Publications 2010/007838; 2010/0084330; and2010/0078381 and International Patent Publication WO 2009/157877 A1,which are incorporated herein by reference. In some embodiments, thedialysate regeneration unit with one or more sorbent cartridges cancontain one or more materials selected from the group consisting of: 1)a urease-containing material, where urease is an enzyme that catalyzesthe conversion of urea to ammonium ions and carbon dioxide; 2) azirconium phosphate (ZrP) material that has the capacity to act as acation exchanger by absorbing a large quantity of ammonium ions inexchange for sodium and hydrogen ions; 3) a zirconium oxide material(ZrO), which acts as an anion exchanger by exchanging phosphate foracetate; and 4) an activated carbon material that has a surface area foradsorption of wide range of impurities including metal ions and uremictoxins, such as uric acid, creatinine, and β2-microglobin. The termzirconium oxide is used interchangeably with the term hydrous zirconiumoxide. In some embodiments, the zirconium phosphate material can bereplaced with a magnesium phosphate material.

In some embodiments, the urease and/or sorbent materials used fordialysate regeneration include a layer of urease and alumina thatconverts urea in spent dialysate into ammonium, which changes theconductivity of the dialysate fluid as the fluid flows through adialysate regeneration unit. The difference in conductivity measured inthe dialysate pre- and post-contact with a urease-containing material iscorrelated to the amount of urea removed during hemodialysis therapy.

The methods disclosed make use of solution conductivity increase thatoccurs as a result of the ionic byproducts of catalytic hydrolysis ofurea by the enzyme urease according to

In some embodiments, a single conductivity meter or detector can measuremultiple flow streams, where each flow stream represents the spentdialysate contacted with a different combination of urease-containingmaterials and/or sorbents, or the spent dialysate prior to any contactwith urease-containing materials and/or sorbents. As such, calibration,temperature, electronic drift and other errors between separateconductivity meters can be reduced or eliminated. The ability to monitorconductivity changes affected by different combinations ofurease-containing materials and/or sorbents allows for the performanceor efficiency of various system components to be evaluated as well asthe determination of the amount of urease in the dialysate.

In certain embodiments, the urease-containing material and additionalsorbent materials are interdispersed within the same housing. Theperformance of conversion of urea to ammonia can be monitored anddetermined by intermittently providing a bolus of a sodium chloridesolution to the dialysate regeneration cartridge such that the ureacontent of spent dialysate entering the regeneration cartridge can bedetermined. In certain embodiments, an equilibration bypass is providedto allow for the dialysate within the dialysate flow loop to come intoequilibration with the urea concentration of the blood in contact withthe dialyzer. After equilibration, the conductivity monitoring systemcan determine the urea content of the equilibrated dialysate, whichreflects the urea content of the blood.

In certain embodiments, the components of the dialysate flow loop canhave a controlled compliant volume. As such, fluid is in passiveequilibrium and does not provide for net flow from the extracorporealcircuit to the dialysate flow loop due to the controlled compliantvolume of the dialysate loop. The net balance of fluid is prevented frompassively flowing between the flow loop to the extracorporeal circuitvia the dialyzer since such a movement of fluid will leave a vacuum inthe flow loop or require the flow loop to expand. Since the dialyzer canbe a high-flux type that readily allows for the passage of water, thereis some fluid flux back and forth across the dialyzer membrane due tothe pressure differential on the blood and dialysate sides of themembrane. This is a localized phenomenon due to the low pressurerequired to move solution across the membrane and is calledbackfiltration; however, this results in no net fluid gain or loss bythe patient.

The components forming the dialysate flow loop of the invention can havea controlled compliant volume wherein the dialysate flow loop furtherincorporates a control or ultrafiltration pump that can be operatedbi-directionally to cause the net movement of fluid from anextracorporeal side of the dialyzer into the dialysis flow loop or tocause net movement of fluid from the dialysate flow loop into theextracorporeal side of the dialyzer. In particular, a control orultrafiltration pump is operated in the efflux direction to cause themovement of fluid from the extracorporeal side of the dialyzer into thedialysis flow loop and in the influx direction to cause the movement offluid from the dialysis flow loop into the extracorporeal side of thedialyzer. The action of typical pumps contemplated by the inventionfunction by expanding or contracting a space wherein any suitable typeof pump can be used in the present invention.

In certain embodiments, operation of the control or ultrafiltration pumpin the influx direction can be substituted with operation of theinfusate pump to drive liquid from the infusate reservoir into thedialysis flow loop and subsequently cause movement of fluid from thedialysis flow loop to the extracorporeal side of the dialyzer. Thecontrol or ultrafiltration pump can also be used for the movement offluid in the opposite direction across the dialyzer into the dialysisflow loop. It is noted that the infusate reservoir or ultrafiltratereservoir can allow the system to adjust the patient fluid volume bywithdrawing fluid and storing the desired amount in the respectivereservoir and/or by providing rebalanced fluids to the patient andremoving waste products. For example, the fluid stored in a controlreservoir attached to the dialysate circuit can be used to store avolume of fluid equal to the ultrafiltrate volume removed from thepatient during ultrafiltration (UF). Alternatively, the fluid stored inthe control reservoir can be an infusate delivered to the patient. Incertain embodiments, the delivered fluid can contain a therapeuticcomponent deliverable across the dialyzer and into the patient'sbloodstream. Additionally, the volume of the dialysate flow loop can beactively controlled by the user or a programmed controller.

The control or ultrafiltration pump allows for fluid to move from thedialysate flow loop to the extracorporeal side without creating avacuum, wherein the operation of the control pump is controlled asdescribed herein. Likewise, the control pump allows for fluid to movefrom the extracorporeal side, and hence the patient's body via theaction of the control pump. Movement of fluid between the extracorporealside of the dialyzer and the dialysate flow loop can be accuratelycontrolled and metered using the removed fluid in certain embodiments.In other embodiments, the removed fluid can be transferred back to thepatient through the dialysate flow loop using the ultrafiltrate storedin ultrafiltration reservoir. In some embodiments, the ultrafiltrationreservoir can be prefilled with water, dialysate or other fluid foraddition to the dialysate flow loop and/or for use or treatment withinthe sodium control system.

As such, some embodiments have a controlled compliant dialysate flowloop that can be accurately controlled to precisely remove or add fluidto the extracorporeal side of the dialyzer. Due to the substantiallyinflexible void volume of the conduits, the dialysate regeneration unitand other components of the dialysate flow loop, the net movement offluid over any time interval across the dialysate membrane within thedialyzer can be accurately controlled by creating a means to accuratelyintroduce or remove fluid from the patient. This capability can furtherbe used to enhance the convective clearance of the system for uremicimpurities while controlling the net fluid removed from the patient, forexample, creating periods of fluid movement across the membrane withoccasional reversal of direction. In certain embodiments, anultrafiltrate can be used as described herein. However, the presentinvention is not limited to a controlled compliant flow path. As such,the dialysate flow loop in certain embodiments is not a controlledcompliant flow path and may include one or more open reservoir forstoring or accumulating dialysate.

In certain embodiments, a control pump can be a peristaltic pump, avolumetric metering pump, diaphragm pump, or a syringe style pump.Hence, the dialysate flow loop has a substantially inflexible volumeexcept for controlled changes in volume modulated by the control orultrafiltration pump, the infusion pump and optionally any other pumpsthat add fluid to the dialysate flow loop. The contents of U.S. patentapplication Ser. No. 13/565,733 filed on Aug. 2, 2012 are incorporatedherein by references in their totality.

In certain embodiments, the dialysate flow loop has a void volume fromabout 0.15 L to about 0.5 L. In other embodiments, the dialysate flowloop has a void volume from about 0.2 L to about 0.4 L or from 0.2 L toabout 0.35 L. Other volumes can be envisioned by those of ordinary skillin the art depending on parameters such as patient weight, size, andhealth condition. The system can be designed to be a portable system, adesktop system or a large system suitable for heavy use in a clinicalsetting. Hence, both large volumes greater than 0.5 L to about 5 L, andmicro-volumes from as small as 0.1 L to about 0.5 L such as 0.1 L to 0.2L, 0.1 L to 0.3 L, 0.1 L to 0.4 L, 0.2 L to 0.3 L, 0.3 L to 0.4 L, or0.3 L to 0.5 L are contemplated by the invention.

Exemplary dialysate flow loops are described in more detail belowincluding in relation to FIGS. 7, 8 and 11 . A dialysate flow loop has adialysate flow path 320 and post-dialyzer flow path 310 for transportinga dialysate between a dialyzer 318 and a dialysate regenerationcartridge or system 100. A bypass loop 308 can be present to allow forthe diversion of a portion of the dialysate around the dialyzer 318 torejoin the flow path in the post-dialyzer 310 flow path. One or moreinfusates can be added by an infusate injector 313, which can be presentto add an infusate to either the dialysate flow path 320 orpost-dialyzer 310 flow paths. Similarly, a buffer pump or sourcesolution 311 can be present for addition to the dialysate flow loopand/or a pump or source for adding fresh water/dialysate 323. Freshwater/dialysate 323 can be added to the dialysate flow loop as a diluentto decrease the conductivity or sodium chloride content of thecirculating dialysate. An ultrafiltration or control pump can also bepresent to add or remove volume from the dialysate flow loop (notshown). Where dilution of the sodium concentration or conductivity ofthe dialysate is needed, water from fresh water or dialysate source 323can be added to the dialysate flow loop and dialysate removed from thedialysate flow loop using the control pump. The control pump can also beused to affect ultrafiltration of the blood by drawing fluid out of theblood through the membrane of the dialyzer 318 and/or the control pumpcan be used to add volume to the dialysate flow loop to counterhemoconcentration within the dialyzer 318.

The systems and methods disclosed herein can be broadly applied todialysis equipment and be used in a blood based solute monitoringsystem. A critical principle utilized by the blood based solutemonitoring system is that a small volume of dialysate can berecirculated through the dialyzer multiple times in a short period oftime to equilibrate a dialysate solute concentration to a blood soluteconcentration on the blood side of a dialyzer in order to obtain certainmeasurements of patient blood solute concentration. In some embodimentsa small void volume dialysate loop with sorbent based regeneration andfluid circulating in a closed loop can take advantage of this criticalprinciple. However, a sorbent is not necessarily required as part of thepresent system where dialysate is recirculated. In other embodiments,addition of a small volume recirculating dialysate loop to a sorbentregenerative dialysis system having an open reservoir, such as a REDYsystem, can make these systems capable of utilizing this principle. Incertain embodiments, a small recirculating loop and a miniature sorbentcolumn can be added to a standard single pass dialysate system to enablethis type of system to be able to utilize the measurement principlesdisclosed. In any embodiment, the dialysate flow rate can be increasedor the volume of the dialysate loop decreased to reduce theequilibration time. In certain embodiments, a measurement can be takenby the present blood based solute monitoring system without a secondflow path that is not equilibrated with blood on the blood side of adialyzer. In other embodiments, the present blood based solutemonitoring system can be in fluid communication with a sorbentregenerated dialysate loop, or a controlled compliant loop. In stillfurther configurations, a small volume recirculation loop with a controlvalve could be installed in a traditional single pass system to takeadvantage of the principles discussed herein. For example, the smallvolume recirculation loop can be installed and in fluid communicationwith a REDY type system or a REDY open reservoir type system.

One of ordinary skill will understand that many systems known within theart can advantageously employ a small recirculating volume toequilibrate the solute concentration quickly across a dialyzer. Becausethe circulating volume in a recirculating flow path is sufficientlysmall, the system can pump in a short period of time the necessaryvolume of fluid to recirculate the fluid through the dialyzer asufficient number of times to equilibrate the concentration of solutesin the dialysate to the concentration of solutes in the blood. One ormore pumps can be configured in the system to reduce equilibration timesor to cause fluid flows through specific fluid paths.

In certain embodiments, the small recirculating volume can be configuredinto a controlled compliant flow path as described herein to reduceequilibration time and/or be configured to be in fluid communicationwith a dialysate flow path that is also controlled compliant. However,it will be understood that the present recirculating loop having small,quickly equilibriated volumes can be configured to be in fluidcommunication with any dialysis machine or therapy device usingcombinations of tubing, one or more valves, and one or more sensors. Atheoretical minimum volume for use in the blood based solute monitoringsystem can be a priming volume of the dialysate compartment of thedialyzer.

Various sensor types can be used to detect the chemical changesoccurring as the dialysate flows through the various sorbent layers.Chemical sensing that operates by fluid conductivity measurement with aconductivity meter can be used. In any embodiment, ion selectivemembranes can be applied to the conductivity electrodes by techniquesthat are known in the art and commercially available, in order tomeasure pH, or other ion species such as sodium and potassium. In someembodiments, additional sensors for measuring pH, temperature, andpressure can be added to one or more flow paths containing theconductivity meter to enhance the measurement accuracy and specificity.The blood based solute monitoring system requires at least onemeasurement. For example, an ion selective sensor such as a potassiumsensor can be used wherein only a single sensor is required and a singlemeasurement is taken to determine the equilibrated dialysateconcentration, and thus the blood concentration. Similarly, a singlesensor reading from an ammonium ion sensor located post-urease can beused to measure BUN. For determining both conductivity and/or a pH-basedmeasurement, at least 2 sensors or 2 fluid samples both before and afterfluid has passed urease are required to obtain BUN. In certainembodiments, the blood based solute monitoring system need not relysolely on equilibration but can utilize an electrolyte bolus to performthe measurement of the blood solute concentration. For example, a bolusis provided between the dialyzer outlet and the sorbent inlet. As shownin the non-limiting, embodiment of FIG. 8 , three sample points and abolus injector are located between the outlet of the sorbent and theinlet of the dialyzer.

In any embodiment, the conductivity monitor of the present invention canbe used to measure urea concentration in the dialysate, further enablingthe determination of blood urea concentration, for example at thebeginning and at the end of a dialysis session, at intermediate timepoints during a dialysis session, at a specific time after the end of adialysis session (to measure rebound of urea, or other solutes, todetermine equilibrated clearance, or eKt), or for determination ofprotein catabolic rate (PCR), a nutritional marker derived frominterdialytic urea accumulation that can be important in determining thedialysis prescription.

In any embodiment, measurement of the urea concentration in thedialysate can further be used to monitor the time course of ureaconcentration decrease, effective dialysance, for deviations that mayindicate deficiencies related to blood access recirculation, accessconnection errors, blood flow inaccuracy, or dialyzer clotting thatrequires intervention within the dialysis session to ensure therapytargets are met. In some embodiments, measurement of the ureaconcentration in the dialysate can further be used to determine totalurea mass clearance for a dialysis session by multiplying ureaconcentration by dialysate flow rate and integrating over dialysissession time to obtain the urea Kt.

FIG. 1 shows a dialysate regeneration cartridge 100 in accordance withcertain embodiments of the invention. The dialysate regenerationcartridge 100 can include a urease material segment or layer in sequencewith one or more sorbent materials. For example, the sorbent cartridge100 illustrated in FIG. 1 includes a segment or layer containing theenzyme urease and alumina 102, a zirconium phosphate segment or layer103, a zirconium oxide segment or layer 104, and an activated carbonsegment or layer 105. In any embodiment, the urease material 102 canalso include alumina. Spent dialysate containing blood impurities, suchas urea, enters the sorbent cartridge 100 through inlet stream 301,passes through the urease material 102 and the sorbent materials, andregenerated or partially regenerated dialysate exits the sorbentcartridge 100 through outlet stream 302. The sorbent materials removethe impurities from the dialysate, and the dialysate returns to thedialyzer through the sorbent outlet stream 302.

Urea can be converted to ammonium carbonate as the dialysate passesthrough the urease layer 102, according to Scheme 1 as described herein.As the solution passes through the urease layer 102, ammonium andbicarbonate ions produced by this reaction can result in an increase indialysate solution conductivity proportional to the concentration ofurea in the dialysate stream entering the regeneration cartridge 100through inlet stream 301.

The dialysate regeneration cartridge 100 of FIG. 1 can be associatedwith a pre-urease conductivity measurement point 201 upstream from theurease material 102 in the dialysate flow loop between a dialyzer outletand the sorbent inlet stream 301, and an integral post-ureaseconductivity measurement point 202 downstream of the urease material102. A measurement point refers to a position in a flow path or sorbentcartridge that is in fluid communication with a sensor. The sensor canbe in fluid communication at a particular position, or measurementpoint, by being physically located at the position of interest, orlocated away from the position of interest and have a fluid stream fromthe position of interest conveyed to the sensor. Conveyance of the fluidstream can occur via flow paths. In any embodiment, the post-ureasemeasurement point can be located downstream from the sorbent outletstream 302 between any stage or stages of the regeneration cartridge 100and a dialyzer inlet. In any embodiment, a controller, such as a digitalprocessor, can monitor the conductivity measurements taken at theconductivity measurement points 201 and 202. The controller can furtherperform calculations using the conductivity measurements and/oradditional measurements, such as the dialysis flow rate taken at thedialysate flow sensor 203, for example, to determine the amount of urearemoved by the urease material 102 over time. The difference between theconductivity measurements at conductivity measurement points 202 and 201can be used to determine the urea concentration of the spent dialysateentering the sorbent cartridge 101 through the inlet stream 301. Theurea concentration can further be multiplied by the dialysate flow rateas measured by flow sensor 203 to determine the urea mass flow ratecleared by the dialyzer.

FIG. 2 shows a dialysate regeneration unit that can include a ureasehousing 101 that contains the urease material 102 and a separate sorbenthousing 106 that can contain one or more sorbent material segments orlayers, for example, the zirconium phosphate segment or layer 103, thezirconium oxide segment or layer 104, and the activated carbon segmentor layer 105. Spent dialysate enters the urease housing 101 through thesorbent cartridge inlet stream 301, passes through the urease material102 and exits the urease housing 101 through the urease housing outletstream 303, then enters the sorbent housing 106 through the sorbenthousing inlet stream 304 and passes through the sorbent materials 103,104, 105 before exiting the sorbent housing 106 by way of the sorbentcartridge outlet stream 302 as regenerated or partially regenerateddialysate.

The dialysate regeneration unit of FIG. 2 can be further associated witha pre-urease conductivity measurement point 201 upstream of the ureasehousing 101 and a post-urease conductivity measurement point 202downstream of the urease housing 101 and upstream of the sorbent housing106. In some embodiments, conductivity measurement point 202 is externalto the urease housing 101 and the sorbent housing 106, which can haveadvantages in certain applications. For example, having the conductivitymeasurement point external to the sorbent cartridge can simplifyplacement of a conductivity sensor directly at the measurement point orsimplify incorporation of a flow path used to convey a fluid stream to asensor positioned at a location different than the measurement point. Insome embodiments, sorbent housing 106 can include multiple layers ofindividual sorbent materials. In other embodiments, sorbent housing 106can contain multiple sorbent materials that are blended together to forma single, uniformly mixed layer. Additional embodiments can includemultiple sorbent cartridge housings that each contain an individualsorbent material. As described in FIG. 1 , a controller can monitor theconductivity measurements taken from the conductivity measurement points201 and 202, and in any embodiment the dialysate flow sensor 203 canmeasure the flow rate of the dialysate, which can be used in furthercomputations.

FIGS. 1 and 2 show exemplary embodiments of dialysate regeneration unitsand are not exclusive. Other types of sorbent materials and othersequences of materials can be provided.

Conductivity Monitoring System

FIG. 3 shows a dialysate regeneration unit or device that can include aurease housing 101 containing, for example, a urease material 102 and asorbent housing 106 containing, for example, one or more sorbentmaterials or other regenerative materials 107 to remove waste speciesfrom the dialysate, such as the sorbent cartridge shown in FIG. 2 . Insome embodiments, the urease housing 101 and the sorbent housing 106 canbe integral to a single unit, such as an interchangeable sorbentcartridge, whereas in other embodiments the urease housing 101 and thesorbent housing 106 can be separate and independent units. Post-dialyzerdialysate, or spent dialysate, can enter the urease housing 101 throughthe sorbent cartridge inlet stream 301, pass through the urease material102 and exit the urease housing 101 through urease housing outlet stream303 before entering the sorbent housing 106 through sorbent housinginlet stream 304, passing through one or more layers of sorbents and/orother regenerative materials 107 in sorbent housing 106 and exiting thesorbent housing 106 through the sorbent cartridge outlet stream 302.Within the sorbent housing, there may be multiple sub-layers ofmaterials of different sorbent compositions, such as illustrated anddescribed for FIGS. 1 and 2 .

The dialysate regeneration unit or device can further include aconductivity monitoring system having a single conductivity meter 204and a sampling valve 401, such as a three-way valve shown in FIG. 3 ,capable of selecting between two separate sample streams 306 or 307 thatare drawn from the junction points 501 or 503, respectively. The singleconductivity meter 204 may alternatively be referred to as “singleconductivity sensor 204”, “common conductivity meter 204”, or “commonconductivity sensor 204.” The junction points 501 and 503 allowdialysate fluid to flow towards conductivity meter 204, depending on theposition of sampling valve 401. The junction points 501 and 503 couldconsist of a 3-way tee-connector. One of ordinary skill in the art willrecognize that junction points 501 and 503 can also include two-wayvalves, which could replace the three-way valve and provide equivalentfunctionality for any of the sampling valves described herein. In someembodiments the sample streams 306 and 307 can convey a continuous flowof dialysate from the selected flow streams 306 or 307, while in otherembodiments the sample streams 306 and 307 can convey an intermittentflow of dialysate.

In any embodiment of the invention, sampling can be accomplished usingtubing or a flow conduit external to or integral to the urease housing101 and sorbent housing 106. The first sample stream 306 can be drawnfrom the post-dialyzer dialysate flow stream 310 upstream of the sorbentcartridge inlet stream 301 before the urease has hydrolyzed the ureainto ionic byproducts, and the second sample stream 307 can be drawnfrom the dialysate flow downstream of the urease housing outlet 303. Insome embodiments, each sample stream can convey a small fraction of themain dialysate flow stream. The sampling valve 401 can be placed in aclosed position to inhibit flow through both sample streams 306 and 307and allow dialysate to flow through the urease and sorbent housings 101and 106 without any sampling.

In order to measure the reduction in the urea concentration of thedialysate when it passes through the urease 102 using the conductivitymonitoring system, the sampling valve 401 can be intermittently toggledbetween a first intake position and a second intake position. Whensampling valve 401 is placed in the first intake position, sample stream306 delivers dialysate to the sampling valve 401 prior to entering theurease housing 101 and/or contacting the urease layer 102; the firstsample stream 306 conveys post-dialyzer dialysate from junction point501, which contains urea that has not yet been converted into ammoniumion species. Dialysate in sample stream 306 can be passed through thesampling valve 401 to a conductivity meter 204 and a first conductivitymeasurement is obtained from the post-dialyzer dialysate before urea ishydrolyzed into ionic by-products.

When first sampling valve 401 is placed in the second intake position,sample stream 307 is delivered to the sampling valve 401 andsubsequently to the conductivity meter 204. The second sample stream 307can be drawn from the dialysate flow after the dialysate has contactedthe urease layer 102 but before the dialysate has contacted anydownstream layers within the sorbent housing 106. More specifically, thesecond sample stream 307 is sampled from junction point 503 aftercontact with the urease layer 102 has been completed and the conversionfrom urea to ammonium salt is substantially complete. In someembodiments, sample stream 307 can be taken from a position at theinterior of an integral sorbent cartridge. For example, sample stream307 may result from a tube inserted part-way into the sorbent cartridgeand in fluid communication with the dialysate flowing through thesorbent cartridge at a point near the urease housing outlet stream 303.In certain embodiments sample stream 307 can be drawn from a junctionpoint between separate and independent urease and sorbent housings 101and 106.

A second conductivity measurement can be taken by conductivity meter 204using the second sample stream 307. Dialysate in sample stream 307 canbe passed through the sampling valve 401 to a conductivity meter 204 anda second conductivity measurement can be obtained for the dialysateafter some or all of the urea has been hydrolyzed into ionic byproducts.

In any embodiment, sampling valve 401 can be periodically alternatedbetween the first sample flow stream 306 and the second sample flowstream 307 and alternating conductivity measurements can be taken by theconductivity meter 204 corresponding to the two sample streams 306 and307 to measure the reduction in the urea concentration of the dialysateaffected by the urease material 102. The period of time for performingthe conductivity readings in various, non-limiting embodiments can beless than 5 minutes, less than 3 minutes, less than 1 minute, less than45 seconds, less than 30 seconds or less than 15 seconds depending oneach separate conductivity measurement. However, it will be understoodthat any period of time is contemplated by the present invention. Incertain embodiments, the sampling valve 401 can remain in a fixedposition until a conductivity reading taken by the conductivity meter204 stabilizes to an acceptable level of drift, rather than remaining ina certain position for a fixed period of time.

The reduction in the concentration of urea in the dialysate resultingfrom the removal of urea as the dialysate passes through the ureasematerial 102 can be determined by comparing the conductivity readingfrom sample stream 307 and the conductivity reading from sample stream306. The monitoring of urea concentration or amount in the dialysate canbe monitored in a real-time manner during the period where the samplingvalve 401 is actively toggled between sample stream 306 and 307.Alternatively, the sampling valve 401 can periodically be placed in theclosed position and conductivity measurements can be intermittentlytaken to determine the urea content of the dialysate on an intermittentbasis.

In addition, any embodiment of the invention can include a dialysateflow sensor 203 to measure the rate of flow of the dialysate passingthrough the dialysate regeneration unit or device. In certainembodiments, the dialysate flow sensor 203 can be located along flowstream 310 to measure the flow rate of dialysate through the dialysateregeneration cartridge 100 or urease housing 101. The measured flow rateof dialysate through the regeneration cartridge 100 or urease housing101 can be used to calculate additional data, for example, incombination with the conductivity readings to quantify the amount ofurea removed from the dialysate by the dialysate regeneration cartridge100 or urease housing 101 during a specified period of time.

After a conductivity reading is taken at conductivity meter 204, thesample stream exiting conductivity meter 204 can be diverted to thebypass loop 308 and rejoined with the working dialysate solution in thedialysate flow loop at a position downstream from the dialyzer andupstream from the dialysate regeneration unit or device. Since a singleconductivity meter 204 is used to measure the conductivity of both thefirst and the second sample streams 306 and 307, offset slope and drifterrors that may occur when comparing measurements taken by two separatesensors can be eliminated. Further, in certain embodiments thermaldifferences between the first and second sample streams 306 and 307 canbe minimized by co-routing and/or insulating the corresponding conduits.In any embodiment, the conductivity meter 204 can be fluid temperaturecompensated by having a thermocouple contained in the conductivitymeter, or in close proximity.

In the embodiment shown in FIG. 3 , the conductivity meter 204 isconfigured to take a conductivity measurement from two separate sampleflow streams, where each flow stream represents a stream having adifferent degree of contact or modification by the dialysateregeneration unit or device. In FIG. 4 , a dialysate regeneration deviceis shown that is capable of measuring three different flow streams 306,307 and 302 using one shared conductivity meter 204.

As described in FIG. 3 , the first sample stream 306 consists ofdialysate prior to contact with the urease-containing layer 102contained in the urease housing 101. The second sample stream 307consists of dialysate after contact with the urease-containing layer 102contained in the urease housing 101. FIG. 4 shows an additionalembodiment where a conductivity measurement can be taken from thesorbent housing outlet flow stream 302 consisting of dialysate that haspassed through all layers of the dialysate regeneration unit, includingthe urease-containing layer 102 and the other sorbent materials 107contained in sorbent housing 106.

In any embodiment an optional sample return buffer reservoir 109 asshown in FIGS. 3-15 can temporarily store the sample fluid before it isreturned to the main dialysate flow loop via bypass loop 308, in orderto prevent returned sample fluid from modifying the composition of fluidin the main dialysate flow loop while a conductivity reading is beingtaken. An optional buffer pump 412 can be operated in conjunction withsampling valve 411 to either transfer fluid exiting the conductivitymeter 204 into the sample return buffer reservoir 109, or to transferfluid from the sample return buffer reservoir 109 to the main fluid loopvia bypass loop 308. In some embodiments, the buffer pump 412 can alsofunction as an ultrafiltration or fluid balance control pump and thesample return buffer reservoir 109 can also serve as an ultrafiltrate orfluid balance control reservoir.

As shown in FIG. 4 , the sampling valve 401 can be alternated between aclosed position and first and second sampling positions to select thefirst 306 or second 307 flow stream, as described above. In the closedposition, dialysate is prevented from entering the conduits forming thefirst 306 and second 307 flow paths.

A common conductivity meter 204 can intermittently measure theconductivity from all three sample streams 306, 307 and 302, as such,errors that can result from calibration differences between separateconductivity meters are eliminated. In addition to measuring urearemoval by comparing conductivity differences between pre- andpost-urease sample streams 306 and 307, the conductivity meter 204 canalso monitor performance of the sorbents within sorbent housing 106 bycomparing conductivity measurements of dialysate fluid from flow stream302 exiting the sorbent housing 106 with conductivity measurements fromthe dialysate fluid taken through the second sampling conduit 307 beforeit has entered the sorbent housing 106 through sorbent housing inlet304. That is, conductivity of the second sample stream 307 can becompared to the conductivity of dialysate flow stream 302 to determineperformance of the materials within the sorbent housing 106. Further,the conductivity of the dialysate flow stream 302 can indicate theactual conductivity of the dialysate entering the dialysate flow loopvia dialysate flow path 320 to determine if overall dialysate sodium ionconcentration is within a predetermined level for the dialysis therapysession.

In the embodiment shown in FIG. 4 , the urea content of the dialysateentering the dialysate regeneration unit can be measured in a real-timeand/or continuous fashion as described in FIG. 3 . However, in someembodiments the conductivity of flow stream 302 is measured during themajority of the period of treatment, for example, 90% of the treatmenttime. To obtain a reading from the first sample flow 306 (pre-ureaseflow), the first sampling valve 401 can be switched to a first samplingposition to allow flow into the bypass conduit 306 and the secondsampling valve 402 can be switched to a position to block flow from theregeneration cartridge outlet 302 from reaching conductivity meter 204.To measure the conductivity of the second sample stream 307, samplingvalve 401 can be switched to the second intake position to allow flowfrom the second sampling conduit 307 while the second sampling valve 402remains switched to allow the sampling flow 307 to pass throughconductivity meter 204 and the post-urease conductivity measurement istaken. As described above with reference to FIG. 3 , the dialysate flowsensor 203 can take dialysate flow rate measurements that can be used tocalculate additional data.

FIG. 5 illustrates a dialysate regeneration unit or device in which theurease material 102 and the regenerative material(s) 107 can becontained in sequential layers within a single housing of the sorbentcartridge 100. In this example, either the pre-urease sample stream 306or a post-urease sample stream 307 can be intermittently directed to thesingle conductivity sensor 204 by way of sampling valve 401 forconductivity measurement. In FIG. 5 , the post-urease sample stream 307is conveyed directly from the interior of the sorbent cartridge 100 atthe interface 505 between the urease material layer 102 and the sorbentmaterial(s) layer 107. Sample stream 307 is conveyed to the exterior ofthe regeneration cartridge 100 by way of a dedicated sampling bypassduct 326. The inlet 305 to the sampling bypass duct 326 is positionedimmediately below the interface 505 between the urease material layer102 and the sorbent material(s) layer 107, to ensure sample stream 307has contacted a majority of the urease material layer 102, but has notcontacted the sorbent material(s) layer 107, which could adverselyaffect the conductivity measurement.

In various embodiments, the sorbent material(s) 107 can consist of asingle material, multiple layers of individual materials, or multipleintermixed materials. In any embodiment in accordance with FIG. 5 , thesampling bypass duct 326 can consist of a segment of metallic, polymericor composite tubing that extends between the urease material 102 and thesorbent material(s) 107 to the exterior of the sorbent cartridge 100. Invarious embodiments, the sampling bypass duct 326 can be a compatiblerigid-wall, flexible or pliable material known in the art. The inlet 305to the sampling bypass duct 326 could also contain a mesh or filtermaterial to prevent urease material 102 from leaving the sorbentcartridge 100.

Thus, the chemical reactions and adsorption occurring in individualsorbent material layers can be monitored independently withoutnecessitating the insertion of a sensor into the cartridge or packagingof the sorbent layers in separate containers joined by connecting fluidconduits. In various embodiments, the sensor can measure differentialconductivity, pH, and/or use optical detection to analyze the dialysate.

In any embodiment in accordance with FIG. 5 , the operation of samplingvalve 401 is equivalent to that described above with reference to FIG. 3. Thus, conductivity measurements can be taken for the pre-urease samplestream 306 and the post-urease sample stream 307 and compared todetermine the performance of the urease material 102 in removing ureafrom the spent dialysate. As described above with reference to FIG. 3 ,the dialysate flow sensor 203 can take dialysate flow rate measurementsthat can be used to calculate additional data.

FIG. 6 depicts a dialysate regeneration unit or device in which theurease material 102 and the sorbent material(s) 107 can be comingled orintermixed in the sorbent cartridge 100. Any embodiment in accordancewith FIG. 6 can intermittently divert a post-dialyzer (pre-urease)sample stream 306 via junction point 501 upstream of the dialysateregeneration sorbent cartridge 100 and a post-regeneration sample stream309 via junction point 507 downstream of the regeneration cartridge 100by way of sampling valve 413 to conductivity sensor 204. The operationof the sampling valve 413 can be equivalent to that described above withreference to FIG. 3 , except that in embodiments in accordance with FIG.6 the difference between the measured conductivity of the post-ureasesample stream 309 and that of the pre-urease sample stream 306 candetermine the differential conductivity across the entire sorbentcartridge 100. For example, the differential conductivity across thesorbent cartridge 100 can be used to monitor the sodium ionconcentration and/or conductivity of the dialysate, which can be used todetermine an appropriate amount of a diluent to be added to thedialysate flow loop to maintain a relatively constant biocompatiblesaline solution.

Ionic dialysance is a method known in the art to effectively quantifyeffective clearance for a dialysis session (Steil et al., Int'l JournArtif Organs, 1993, In Vivo Verification of an Automatic NoninvasiveSystem for Real Time Kt Evaluation, ASAIO J., 1993, 39:M348-52, which isincorporated herein by reference). Periodic sodium ion boluses can bedirected through the dialysate regeneration sorbent cartridge 100 tocalculate the effective ionic clearance based upon the changes in pre-and post-dialyzer conductivity measurements during the bolus. Themeasurements can be taken multiple times during a hemodialysis sessionand integrated to measure session “Kt”. By this method, errors due tofactors that change the clearance rate (clearance variability betweendialyzers, blood access recirculation, blood flow rate errors, dialyzerclogging, access connection reversal, dialysis session interruptions)can be eliminated. Because sodium and urea have nearly identicalclearances, a conductive dialysance measurement with sodium boluses hasbeen demonstrated to be a surrogate for urea clearance. The generalmethod for measuring effective dialysance by means of a bolus andconductivity measurements is as follows, with reference to FIG. 7 andany other figures with like component numbers:

-   -   1. Measure initial conductivity at dialyzer inlet 314 (Cd_(i1)).    -   2. Measure initial conductivity at dialyzer outlet 315        (Cd_(o1)).    -   3. Introduce electrolyte concentrate or diluent to the dialysate        stream in order to create a bolus shift in the electrolyte        concentration and corresponding conductivity level.    -   4. Measure bolus conductivity at dialyzer inlet 314 (Cd_(i2)).    -   5. Measure bolus conductivity at dialyzer outlet 315 (Cd_(o2)).    -   6. Calculate effective clearance (K_(eff)). The effective        clearance is calculated according to Equation 2.

$\begin{matrix}{K_{eff} = {Q_{d}*\frac{\left( {{Cd}_{i1} - {Cd}_{o1}} \right) - \left( {{Cd}_{i2} - {Cd}_{o2}} \right)}{\left( {{Cd}_{i1} - {Cd}_{i2}} \right)}}} & \left( {{Equation}2} \right)\end{matrix}$

K can be calculated using Equation 3 below using dialysate flow rate(Q_(d)), concentration in the dialysate entering the dialyzer (Cd_(i))and the concentration in the dialysate exiting the dialyzer (Cd_(o)) andconcentration in the blood entering the dialyzer (Cb_(i)).

$\begin{matrix}{K = {Q_{d}*\frac{{Cd}_{o} - {Cd}_{i}}{{Cb}_{i} - {Cd}_{i}}}} & \left( {{Equation}3} \right)\end{matrix}$

Since the concentration of urea entering the dialyzer is zero, thisrelationship can be reduced to

$\begin{matrix}{K = {Q_{d}*\frac{{Cd}_{o}}{{Cb}_{i}}}} & \left( {{Equation}4} \right)\end{matrix}$

or rearranged as Equation 5

$\begin{matrix}{{Cb}_{i} = {\frac{Q_{d}*{Cd}_{o}}{K}.}} & \left( {{Equation}5} \right)\end{matrix}$

The dialysate flow rate is readily measured by means such as a flowmeter 203 shown in various figures. The effective clearance can bedetermined as described above and with equation 2, by ionic dialysancemeasurements. The effective clearance determined with ionic dialysanceis essentially equal to the clearance (K) for urea. Therefore, bydetermining the dialysate flow rate (Q_(d)) and the urea concentrationof the dialysate exiting the dialyzer (Cd_(o)) the blood concentrationof urea entering the dialyzer (Cb_(i)) can be determined. The ureaconcentration of the dialysate exiting from the dialyzer outlet can bemeasured by comparison of the conductivity of sample streams 306 and307, shown in various figures and described above.

FIG. 7 shows a dialysate regeneration unit or device in which the ureasematerial 102 and the sorbent material(s) 107 can be contained insequential layers within the regeneration cartridge 100, similar to theconfiguration described above with reference to FIG. 5 . However, inembodiments in accordance with FIG. 7 , four different sample streams306, 307, 309, 312 can be diverted from various points in the dialysateflow path to the single conductivity sensor 204 by way of the samplingvalves 401, 414 and 404 for intermittent conductivity measurement. Thefirst sample stream 306 can be diverted from the post-dialyzer(pre-urease) sample stream 310 via junction 501 and intermittentlydirected to the conductivity sensor 204 by way of sampling valves 401and 404 for conductivity measurement. The second sample stream 307,which consists of dialysate that has passed through the urease materiallayer 102 can be collected as described above through the samplingbypass duct 326 and intermittently directed to the conductivity sensor204 by way of sampling valves 401 and 404 for conductivity measurement.The third sample stream 309, which consists of dialysate that has passedthrough sorbent cartridge 100 can be collected through junction 511 andintermittently directed to the single conductivity sensor 204 by way ofsampling valves 414 and 404 for conductivity measurement. The fourthsample stream 312, which consists of dialysate exiting the dialyzer 318can be collected through junction 513 and intermittently directed to thesingle conductivity sensor 204 by way of sampling valves 414 and 404 forconductivity measurement. In this respect, in any embodiment inaccordance with FIG. 7 sampling valve 401 can be configured to close offflow from sample stream 307 and allow flow from sample stream 306, orvice versa. Also, sampling valve 404 can be configured to close off flowfrom stream 521 and allow flow from stream 519, or vice versa. Finally,sampling valve 414 can be configured to close off flow from samplestream 312 and allow flow from sample stream 309, or vice versa.

Similarly, with reference to FIG. 7 , the second, post-urease, samplestream 307 can be diverted from the urease material 102 near theinterface 505 between the urease material 102 and the sorbentmaterial(s) 107 and intermittently directed to the single conductivitysensor 204 by way of the sampling bypass duct 326, sampling valve 401and sampling valve 404 for conductivity measurement. In this case,sampling valve 401 can be configured to close off flow from samplestream 306 and allow flow from sample stream 307, while sampling valve404 simultaneously is configured to close off flow from stream 519 andallow flow from stream 521 to the single conductivity sensor 204. Withfurther reference to FIG. 7 the pre-urease conductivity (C_(pre-U)) canbe obtained by switching valves 401 and 404 to permit the first samplestream 306 to flow through the conductivity meter 204. Post-ureaseconductivity (C_(post-U)) can be obtained by switching valve 401 toallow the second sample stream 307 to flow through the conductivitymeter 204 to measure the conductivity of fluid exiting the ureasematerial 102.

The post sorbent cartridge sample stream 302 of FIG. 7 can be diverteddownstream of the sorbent cartridge 100 via junction 511 andintermittently directed to the conductivity sensor 204 by way ofsampling valve 414 and sampling valve 404 for measurement of thedialysate or bolus conductivity at the dialyzer inlet 314. In order toaccomplish this, sampling valve 414 can be configured to close off flowfrom sample stream 312 at the dialyzer outlet 315 and allow flow fromsample stream 309, while sampling valve 404 simultaneously is configuredto close off flow from sampling valve 401 and allow flow from samplingvalve 414 to the conductivity sensor 204.

In addition, any embodiment can incorporate an infusate injector 313,downstream of the dialyzer and upstream of the sorbent cartridge 100that can add one or more infusates to the dialysate, such as a bufferingagent or other components typically employed to compose a dialysatesolution. The infusate injector 313 can consist of a reservoircontaining an infusate and a pump to deliver the infusate to thedialysate flow loop via junction 515. Alternatively, the infusateinjector 313 may be located in other locations on the dialysate flowloop. In order to facilitate the determination of the conductivitychange contributed by the infusate from the infusate injector 313, asample stream 312 can be diverted downstream of the dialyzer 318 andupstream of the infusate injector 313 and intermittently directed to theconductivity sensor 204 by way of sampling valve 414 and sampling valve404. In order to accomplish the conductivity measurement of samplestream 312, sampling valve 414 can be configured to close off flow fromsample stream 309 and allow flow from sample stream 312, while samplingvalve 404 simultaneously is configured to close off flow from samplingvalve 401 and allow flow from sampling valve 414 to the conductivitysensor 204.

Conductivity measurements taken from sample stream 312 can then becompared to those of sample stream 306, which can be taken as describedabove, to determine the conductivity change resulting from the additionof the infusates to the spent dialysate. Likewise, conductivitymeasurements taken from sample stream 312 can also be compared to thoseof sample stream 309, which can be taken as described above, todetermine the performance or efficiency of the dialyzer 318 with respectto the removal of impurities and waste products from the bloodstreamentering inlet stream 316 and exiting outlet stream 317 of the dialyzer318. As described above, measurements of the dialysate flow rate takenat flow rate sensor 203 can be used to calculate the total amount ofinfusates added to the dialysate or the total amount of impurities andwaste products removed from the bloodstream over time.

Further, the embodiment of FIG. 7 can be advantageously applied to ionicdialysance measurements as describe above in connection to FIG. 6 . Asdescribe above, the system described in FIG. 7 can be used toalternately measure four different sample streams using singleconductivity sensor 204, which can be summarized as follows: pre-ureaseor first sample stream 306, post-urease or second sample stream 307,pre-dialyzer or third sample stream 309 and post-dialyzer or fourthsample stream 312. Ionic dialysance measurements can be accomplished byselectively modifying the rate of introduction of an infusate byinfusate injector 313. Initial conductivity (Cd_(i1)) at the dialyzerinlet 314 can be obtained by switching valves 414 and 404 to permit thethird sample stream 309 to flow through the conductivity meter 204 toindicate conductivity at the dialyzer inlet 314 prior to introduction ofan electrolyte bolus or diluent. The initial conductivity (Cd_(o1)) atthe dialyzer outlet 315 can be obtained by switching valve 414 and 404to permit the fourth sample stream 312 to flow through the conductivitymeter 204 to indicate conductivity of the stream at the dialyzer outlet315 prior to introduction of an infusate from the infusate injector 313.

With reference to FIG. 7 , conductivity measurements for ionicdialysance can be obtained through the following operations. Additionalconductivity measurements can then be obtained by initiating anelectrolyte bolus (or diluent bolus) from the infusate injector 313 toallow an altered conductivity at the dialyzer inlet 314 and outlet 315of the dialyzer to be obtained. A bolus can be initiated by switchingvalves 414 and 404 to allow for the third sample stream 309 to flowthrough the conductivity meter 204 and an infusate is introduced byinfusate injector 313 to either raise or lower the electrolyteconcentration in dialysate stream 310. Bolus conductivity (Cd_(i2)) atthe dialyzer inlet can then be obtained by continuing to measureconductivity with valves 414 and 404 set to allow the third samplestream 309 to flow into the conductivity senor 204 until a minimum ormaximum conductivity is detected in response to the bolus introduced byinfusate injector 313. After a minimum or maximum conductivity forCd_(i2) is detected in response to the bolus, valve 414 is switched toallow the fourth sample stream 312 to be directed toward conductivitymeter 204 and the bolus conductivity at the dialyzer outlet (Cd_(o2)) isobtained when a minimum or maximum conductivity is observed.

Upon obtaining conductivity values Cd_(i1), Cd_(o1), Cd_(i2), andCd_(i2), effective clearance can be calculated using Equation 2 above.The dialysate flow rate (Qd) can be obtained from flow sensor 203. Oneskilled in the art will understand that pre-(C_(pre-U)) and post-urease(C_(post-U)) are not needed for the calculation of effective clearance(K_(eff)). As such, the dialysate regeneration unit can containintermixed sorbent and/or urease materials as shown in FIG. 6 whileallowing for ionic dialysance measurements to be taken. Further, bloodurea concentration can be calculated using Equation 5 upon calculatingthe value of urea in the dialysate exiting the dialyzer (Cd_(o)) usingthe pre- and post-urease conductivity measurements.

As shown in FIG. 8 , any embodiment can incorporate an infusate injector311 downstream of the sorbent cartridge 100 and upstream of the dialyzer318 that can add one or more infusates to the dialysate, such aspotassium ion, calcium ions, magnesium ions or other componentstypically employed to compose a dialysate solution. In order tofacilitate the determination of the overall conductivity changeresulting from the removal of impurities and waste products by thesorbent materials 107 in the sorbent cartridge 100 and the addition ofthe infusates by infusate injector 311, the sample stream 319 can bediverted downstream of the sorbent cartridge 100 and infusate injector311 and upstream of the dialyzer 318 with junction 527 andintermittently directed to the single conductivity sensor 204 by way ofsampling valve 405. Infusate injector 311 is the same as infusateinjector 313, shown in FIG. 7 , except for its position along thedialysate flow loop.

In order to accomplish the conductivity measurement of sample stream319, sampling valve 405 can be configured to close off flow fromsampling valve 401 and allow flow from sample stream 319 to the singleconductivity sensor 204. Conductivity measurements from sample stream319 can be compared to those from sample stream 306 or sample stream307, taken as described above with reference to FIG. 7 in order todetermine the overall conductivity change resulting from the removal ofimpurities and waste products by the sorbent materials 107 in thesorbent cartridge 100 and the addition of the infusates by infusateinjector 311. Similarly, conductivity measurements from sample stream319 can be compared to those from sample stream 307, also taken asdescribed above with reference to FIG. 7 in order to determine theoverall conductivity change resulting from the removal of impurities andwaste products by both the urea material 102 and the sorbent materials107 as well as from the addition of the infusates by infusate injector311. Urea content can be determined by comparing the conductivity ofsample streams 306 and 307 as described for FIG. 3 .

As in FIG. 7 , the embodiment shown in FIG. 8 can be used to obtainionic dialysance measurements for use in conjunction with Equations 2-5.Initial conductivity (Cd_(i1)) at the dialyzer inlet 314 can be obtainedby switching valve 405 to permit the third sample stream 319 to flowthrough the conductivity meter 204. Initial conductivity (Cd_(o1)) atthe dialyzer outlet 315 can be obtained by switching valves 401 and 405to permit the first sample stream 306 to flow through the conductivitymeter 204. Since the infusate injector 311 is not located between thedialyzer outlet 315 and the inlet 301 of the sorbent cartridge 100, thefirst sample stream 306 indicates the conductivity of the spentdialysate exiting the dialyzer.

A bolus can be initiated by switching valves 401 and 405 to allow forthe third sample stream 319 to flow through the single conductivitysensor 204 and an infusate (bolus) is introduced by infusate injector311 to either raise or lower the electrolyte concentration in thedialysate flow path 320. Bolus conductivity (Cd_(i2)) at the dialyzerinlet 314 can then be obtained by continuing to measure conductivity ofthe third sample stream 319 until a minimum or maximum conductivity isdetected in response to the bolus introduced by infusate injector 311.After a minimum or maximum conductivity (Cd_(i2)) at the dialyzer inlet314 is detected in response to the bolus, valves 401 and 405 areswitched to allow the first sample stream 306 to be directed toward thesingle conductivity sensor 204 and the bolus conductivity (Cd_(o2)) atthe dialyzer outlet 315 is obtained when a minimum or maximumconductivity is observed.

Upon obtaining conductivity values for Cd_(i1), Cd_(o1), Cd_(i2), andCd_(i2), effective clearance can be calculated using Equation 2 above.The dialysate flow rate (Qd) can be obtained from flow sensor 203. Asexplained above, all of the values indicated by Equations 2-5 can becalculated from the obtained conductivity data.

Further, any embodiment can incorporate a modified sorbent cartridge 110that includes one or more sorbent materials 108, such as ahighly-selective ion exchange resin, for example, selective for calciumions and/or magnesium ions, upstream of the urease material 102 and anadditional one or more sorbent materials 107 as shown in FIG. 9 . Inlayer 108, the selective resin releases hydrogen ions (H⁺) in exchangefor calcium (Ca²⁺) and magnesium (Mg²⁺), which acts to acidify thesolution and promotes the conversion of ammonia to ammonium afterenzymatic urea breakdown occurs in the urease material 102. The sorbentcartridge 110 can include a post-urease sampling bypass duct 326,equivalent to that described above with reference to FIG. 5 , as well asan additional dedicated sampling bypass duct 321, similar inconstruction to sampling bypass duct 326, but downstream of the sorbentmaterial(s) 108 and upstream of the urease material 102. A sample stream322 can be conducted from sampling bypass duct 321 with inlet 531positioned immediately below the interface 533 between the ureasematerial layer 102 and the sorbent material(s) layer 108, to ensuresample stream 322 has contacted a majority of the sorbent material layer108, but has not contacted the urease material(s) layer 102, which couldadversely affect the conductivity measurement.

In order to measure the conductivity of sample stream 322 in FIG. 9 ,sampling valve 406 can be configured to close off flow from samplestream 307 and allow flow from sample stream 322 to the singleconductivity sensor 204. Conductivity measurements from sample stream307, taken as described above with reference to FIG. 5 with thesubstitution of sampling valve 406 directing the flows from samplestream 322 and sample stream 307 in place of sampling valve 401directing the flows from sample stream 306 and sampling stream 307 inorder to determine the conductivity change resulting from the removal ofimpurities and waste products by the urease material 102 in the modifiedsorbent cartridge 110. As will be understood by one of ordinary skill inthe art, the modified sorbent cartridge 110 described in FIG. 9 can becombined with any of the additional sampling configurations external tothe sorbent cartridge 100 described herein, to configure additionalembodiments of the invention.

Any embodiment of the invention can include a sorbent cartridge bypassflow path 330 as shown in FIG. 10 . The sorbent cartridge bypass flowpath 330 can be diverted from the upstream dialysate flow path 310 andrejoin at the dialysate flow path 320 downstream of the sorbentcartridge 100. The sorbent cartridge bypass flow path 330 canincorporate a bypass valve 407, which, for example, may be a three-wayvalve, as depicted in FIG. 10 , or a combination of two-way valves. Oneskilled in the art will appreciate that the bypass valve 407 can beplaced as shown in FIG. 10 , as well as at an intermediate point withinthe sorbent cartridge bypass flow path 330 or at the downstream junction535. Thus, the sorbent cartridge bypass flow path 330 can inhibit theflow of dialysate through the sorbent cartridge 100 while continuing tocirculate dialysate flow through the dialyzer. For example, the bypassflow path 330 can be utilized to facilitate equilibration of thedialysate concentration of urea and other impurities and waste productswith the concentration of these components in the blood passing throughthe dialyzer.

As described in connection with FIG. 3 , measurement of the ureaconcentration of the dialysate in the post-dialyzer segment 310 of thedialysate flow loop can be used to calculate and monitor clearance Kt.However, an indication of the urea content of the fluid within thedialyzer is not directly provided. During active dialysis, aconcentration gradient between the dialysate and the blood is maintainedto establish hemodialysis treatment. The size of the gradient depends onseveral factors, as such, measurement of dialysate urea content does notallow for a direct measurement to be made of the urea content of theblood. When bypass flow 330 is operated, hemodialysis treatment issuspended as the dialysate comes into equilibrium with the blood and theconcentration gradient of urea and other solutes between the blood andthe dialysate approaches zero. After several passes of the dialysatethrough the bypass flow 330, the dialysate urea concentration willreflect the blood urea concentration. When valve 307 is operated tore-establish dialysate flow through the sorbent cartridge 100, thesingle conductivity sensor 204 can be used to determine the performanceof the urease-containing material as well as other sorbents to evaluatethe content of the dialysate, which is in temporary equilibrium with theblood. As such, the system can be used to periodically determine theurea content of the blood followed by a return to hemodialysistreatment.

Blood urea concentration or BUN and dialyzer clearance (K) can bemeasured as follows using the embodiment shown in FIG. 10 . Pre-ureaseconductivity (C_(pre-U1)) can be measured by switching valve 401 topermit the first sample stream 306 to flow to the single conductivitysensor 204 while valve 407 directs the dialysate stream 301 throughjunction 501 and through the sorbent cartridge 100. Initial post-ureaseconductivity (C_(post-U1)) is measured by switching valve 401 to allowthe second sample stream 307 to flow through the conductivity meter 204and a conductivity measurement is obtained as described above for FIG. 5.

Dialysate urea concentration exiting the dialyzer (Cd_(o)) is determinedby the conductivity difference between measurements Cd_(pre-U1) andCd_(post-U1). Dialysate flow sensor 203 can be used to obtain thedialysate flow rate (Qd).

Dialysate urea concentration is then equilibrated to blood ureaconcentration by switching valve 407 in FIG. 10 to divert the dialysateflow through sorbent bypass loop 330 to cause the dialysate to start therecirculating and equilibration process for a predetermined number ofrecirculation passes. Alternatively, conductivity of first sample stream306 can be observed at conductivity meter 204 until it stabilizes, whichwill indicate that equilibration has occurred between blood anddialysate. With urea equilibrated between blood and dialysate,pre-urease conductivity (C_(pre-U2)) is measured by switching valve 401to direct the first sample stream 306 through conductivity meter 204 andthe conductivity measurement of the equilibrated dialysate stream 310 isrecorded. The conductivity measurement can be recorded by means wellknown to those skilled in the art such as with a computer. With ureaequilibrated between blood and dialysate, post-urease conductivity(C_(post-U2)) is measured by switching valve 407 to stop the bypassre-circulation and direct the flow of urea-equilibrated dialysatethrough sorbent cartridge 100. At the same time, valve 401 is switchedto direct the second sample stream 307 to conductivity meter 204 and theconductivity measurement is recorded.

To calculate the patient's blood urea concentration (C_(bi)), theconductivity difference between C_(pre-U2) and C_(post-U2) can becorrelated to urea concentration as indicated in Scheme 1. Clearance canbe calculated according Equation 4 by using the blood urea concentrationas C_(bi) determined in the preceding step and using the differencebetween the conductivity readings (C_(dpost-U1)-C_(dpre-U1)) todetermine dialyzer outlet urea concentration Cd_(o). It should be notedthat individual conductivity measurements such as the equilibrated ureaconcentration can be performed differently and can be optionallymeasured before any dialysis has altered the patient's BUN.

The examples of FIGS. 3-10 show how the sorbent cartridge 100 or 110 canbe used for urea sensing in conjunction with a hemodialysis fluidcircuit. Further, in certain embodiments the fluid circuit may beconfigured for hemofiltration, hemodiafiltration, or peritonealdialysis. For example, FIG. 11 shows how the sorbent cartridge 100 canbe utilized in a hemofiltration circuit to measure approximate bloodurea concentration, dialysate urea concentration, and urea removal. Thesorbent cartridge 100 includes a urease material 102 and a sorbentmaterial 107. The sorbent cartridge outlet 302 is directed to areplacement fluid flow path 328. A single conductivity sensor 204 isused to measure the conductivity of the dialyzer effluent flow path 327via the sampling streams 306 and 307 before and after the dialysatepasses through the urease layer 102. Since ultrafiltrate hasapproximately the same urea concentration as whole blood, the subject'sapproximate BUN can be determined by measuring the conductivity changeof the filtrate across the urease material 102. The urea concentrationof the filtrate stream 310 can be measured and multiplied by thefiltration rate measured by the flow sensor 203 to determine the urearemoval rate. The measurement method described can be repeated throughthe course of a therapy session and integrated to calculate the totalurea removed during therapy.

FIG. 12 shows how the sorbent cartridge 100 can be utilized in ahemodiafiltration circuit to measure blood urea concentration, dialysateurea concentration, and urea removal. The sorbent cartridge 100 includesa urease material 102 optionally configured as a layer and a sorbentmaterial 107 optionally configured as a layer. The control pump 415 canbe operated to transfer a fluid bolus from the replacement fluidreservoir 328 into the dialysate flow path 320 or to transfer dialysatefrom the dialysate flow path 320 to the replacement fluid reservoir 537.The common conductivity meter 204 measures the conductivity of thedialyzer effluent flow path 327 via the sampling streams 306, 307 beforeand after the dialysate passes through the urease layer 102 as describedin FIG. 10 . The effluent flow rate is measured at the flow sensor 203,and blood urea concentration or BUN can be calculated at the start ofthe therapy session, or at any time during the therapy session asdescribed in FIG. 10 .

FIG. 13 shows a configuration for using the sorbent cartridge 100 tomeasure the patient's urea concentration, spent dialysate ureaconcentration, and total urea removal in a peritoneal dialysis circuit.The sorbent cartridge 100 includes a urease material 102 and a sorbentmaterial 107. A common conductivity meter 204 measures conductivity ofthe dialysate stream 310 before and after passing through the ureasecontaining layer 102. In various embodiments, the dialysate flow sensor203 or the speed of pump 417 can measure the flow rate of the effluent.The injection pump 416 can be operated to transfer dialysate from thedialysate reservoir 111 into the peritoneal cavity 500 of a subject andthe extraction pump 417 can be operated to transfer dialysate from theperitoneal cavity 500 into the main dialysate flow path 310 for returnto the sorbent cartridge 100. The dialysate reservoir 111 can be anexpandable reservoir that temporarily stores the purified dialysateexiting sorbent cartridge 100 downstream of the sorbent outlet flow path302. In any embodiment, the purified dialysate can be rebalanced withprescribed concentrations of electrolytes either before or afterreservoir 111.

If the dialysate dwell time in the peritoneal cavity 500 is sufficientlylong, the dialysate can equilibrate to the subject blood ureaconcentration and the blood urea concentration or BUN can be determinedby measuring the conductivity change of the dialysate across the ureasecontaining layer 102 as described for FIG. 10 . The urea concentrationof the main filtrate flow path 310 can be measured and multiplied by thedialysate flow rate measured by flow sensor 203 to determine the urearemoval rate. Multiple such measurements can be repeated through thecourse of a therapy session and integrated to measure total urearemoved.

FIG. 14 shows an embodiment employing a sorbent cartridge 110 similar tothat shown in FIG. 9 having a sorbent layer 108 containing an ionexchange resin highly selective to Ca²⁺ and Mg²⁺ and releasing H⁺ inexchange. Valves 408 and 409 alternate the first sample stream 306,second sample stream 322, and third sample stream 307 through a singleor common conductivity meter 204 to obtain a precise conductivitydifference between the fluid passing through the three sample streams,as follows: first sample stream 306 (post-dialyzer); second samplestream 322 (pre-urease); and third sample stream 307 (post-urease).Also, the flow diagram shown in FIG. 14 includes a sorbent cartridgebypass flow path 330 as described above for FIGS. 10 and 12 .

In addition to BUN, total blood concentration of calcium and magnesiumions can also be determined. The first sorbent layer 108 contains acation exchange resin highly selective for removal of the divalent Ca²⁺and Mg²⁺ ions from the dialysate stream, such that substantially allCa²⁺ and Mg²⁺ ions are removed, but only an insignificant proportion ofthe other cations such as potassium and sodium are removed by layer 108.An example of such a material is a chelating cation exchange resin. Anexample of a commercially available chelating cation exchange resin isChelex® 100 from Bio-Rad Laboratories, Hercules, Calif. This cationexchange can be expressed according to the following Scheme 2.

The electrolytic conductivity of a single H⁺ ion is approximatelythree-times greater than the electrolytic conductivity of individualCa²⁺ and Mg²⁺ ions being removed by sorbent layer 108. Further, sincetwo H⁺ ions are released for each Ca²⁺ or Mg²⁺ ion removed, theelectrolytic conductivity of the ions exchanged is on the order ofsix-times greater at the outlet of sorbent layer 108 than at the inletto sorbent layer 108. This creates a readily measured conductivityincrease that is proportional to the total amount of the total combineddivalent Ca²⁺ and Mg²⁺ ions in the dialysate stream in the post dialyzerdialysate flow.

Measurement of the total combined blood concentration of Calcium andMagnesium and also the BUN are performed as follows. Dialysate soluteconcentration is equilibrated to blood solute concentration by switchingvalve 409 to divert the dialysate flow through sorbent bypass loop 330to cause the dialysate to start the recirculating and equilibrationprocess and continues to recirculate for a predetermined number ofrecirculation passes. Alternatively, valves 408 and 409 can bepositioned to pass the first sample stream 306 to conductivity meter 204and the conductivity reading observed until it stabilizes, which willindicate that equilibration has occurred between blood and dialysate.With solutes now equilibrated between blood and dialysate, post-dialyzerconductivity (C_(post-dialyzer)) is measured by switching valves 408 and409 to direct the first sample stream 306 through conductivity meter 204and the conductivity measurement of the equilibrated dialysate stream310 is recorded. With solutes equilibrated between blood and dialysate,pre-urease conductivity (C_(pre-U)) is measured by switching valve 409to stop the bypass re-circulation and to direct the flow ofurea-equilibrated dialysate to enter dialysate regeneration unit 110through inlet 301. At the same time, valve 408 is switched to direct thesecond sample stream 322 to conductivity meter 204 and the pre-ureaseconductivity measurement is recorded.

With solutes equilibrated between blood and dialysate, post-ureaseconductivity (C_(post-u)) is measured by switching valve 409 to directthe sample stream 307 through conductivity meter 204 and the post-ureaseconductivity measurement is recorded. Because the dialysate and bloodsolutes are equilibrated, the patient's total combined bloodconcentration of calcium and magnesium is now determined by theconductivity increase between observations C_(post-dialyzer) andC_(pre-U).

Because the dialysate and blood urea are equilibrated, the patient'sblood urea concentration can be determined by the conductivity increasebetween observations C_(pre-U) and C_(post-U) according to Scheme 1. Theeffective clearance, K_(eff), of either the urea or calcium/magnesiumcan be further calculated by taking a second set of conductivityreadings from each sample stream in the non-equilibrated state and thenusing the ionic dialysance method of Equation 2 to calculate K_(eff) forurea as explained in relation to FIG. 9 . If the infusates containingcalcium and magnesium ions are stopped when the second set of readingsare taken, then Equation 2 can also be used to determine K_(eff) forcalcium and magnesium. If the infusates containing calcium and magnesiumwere not turned off during the second set of conductivity readings, butinstead being infused at a known concentration by a sufficientlyaccurate metering system, then equation 3 can be used to determine theK_(eff) for calcium and magnesium. The K_(eff) for urea and calcium andmagnesium can be measured periodically throughout a therapy session andchanges in the K_(eff) can be used to determine issues with the therapy.For example, declines in K_(eff) could indicate the occurrence of accessrecirculation and/or poor blood flow from the access and/or clotting orclogging of the dialyzer and/or dialysate flow error and/or blood flowerror. Some methods for determining the underlying cause of a decreasein K_(eff) can include increasing the patient's anticoagulant dose toreduce clotting of the dialyzer. Also, the blood and/or dialysate flowcould be increased to determine their effect on K_(eff) and if necessarymaintained at higher flow rates in order to achieve a desired K_(eff).

As shown in FIG. 14 , It will be understood that the number ofconductivity measurements can depend upon the number of material layersused in the sorbent system. Hence, a fourth measurement can be taken toobtain the concentration of a third solute, a fifth measurement toobtain the concentration of a fourth solute, and so on until allmaterial layers and sensor types in the sorbent system have beenmeasured. Conductivity measurement across additional sorbent layers willrequire additional sampling bypass ducts similar to sampling bypass duct321 and 326 at the new material interfaces (not shown). Also, additionalsampling valves, similar to 408 and 409 will be required (not shown) todivert the new sample streams to the conductivity sensor 204.

As shown in FIG. 15 , any embodiment of the invention can combinevarious concepts described herein with a fresh water/dialysate source323 to dilute the dialysate. The fresh water/dialysate source 323 canconsist of a reservoir containing water and a pump to deliver water tothe dialysate flow loop. Non-limiting types of water that can be usedinclude tap water, potable water, bottled water, deionized water anddistilled water. For example, the fresh water/dialysate source 323 canenter the dialysate at a junction point 537 downstream of the dialyzer318 and the infusate injector 313 and upstream of the sorbent cartridge100, as depicted in FIG. 15 . One skilled in the art will recognize thatadditional configurations can be used in certain embodiments of theinvention, for example, the fresh water/dialysate source 323 can enterthe dialysate at a junction point downstream of the dialyzer 318 andupstream of the infusate injector 313.

In combination with the fresh water/dialysate source 323, a pre-watersource sample stream 324 and a post-water source sample stream 325 canbe incorporated into the dialysate flow path 310 and directed to theconductivity sensor 204 by way of a sampling valve 421, such as thethree-way valve shown in FIG. 15 . The flow from sampling valve 421 canbe further directed to the conductivity sensor 204 by way of samplingvalve 418 and sampling valve 419, facilitating conductivity measurementfrom at least five junction points along the dialysate flow path 310 and320. Of course, one skilled in the art will recognize that conductivitymeasurements can be taken from any number of sample streams along thedialysate flow path using a single conductivity sensor 204 byconfiguring additional sampling valves in a similar manner.

As further shown in FIG. 15 , any embodiment of the invention cancombine various concepts described herein with a buffer source 311 tochange the buffer concentration of the dialysate. The buffer source 311can consist of a reservoir containing a buffer solution and a pump todeliver the buffer source to the dialysate flow loop. Non-limiting typesof buffer source that can be used include aqueous solutions ofbicarbonate, lactate and acetate. For example, the buffer source 311 canenter the dialysate at a junction point 539 upstream of the dialyzer 318and downstream of the sorbent cartridge 100, as depicted in FIG. 15 .One skilled in the art will recognize that additional configurations canbe used in certain embodiments of the invention, for example, the buffersource 311 can enter the dialysate at a junction point downstream of thedialyzer 318 and upstream of the fresh water/dialysate source 323.

In combination with the buffer source 311, a pre-buffer source samplestream 309 and a post-buffer source sample stream 319 can beincorporated into the dialysate flow path 320 and directed to the singleconductivity sensor 204 by way of sampling valves 418, 419, and 420.

Thus, conductivity measurements can be taken from sample streams 309,319, 312 by configuring the corresponding sampling valves 418, 419, 420as described above with reference to FIG. 7 , with the substitution ofthe sampling valves 418, 419, 420 for the sampling valves 401, 414, 404,respectively. In addition, conductivity measurements can be taken fromsample stream 324 by configuring sampling valve 421 to close off flowfrom sample stream 325 and allow flow from sample stream 324, whileconfiguring the downstream sampling valves 418 and 419 to close off flowfrom sample streams 309 and 319 and allow flow from sampling valve 421to the conductivity sensor 204. Conductivity measurements from sample indialysate conductivity resulting from dilution of the dialysate withwater from the fresh water/dialysate source 323.

FIG. 16 is a simplified flow diagram for a controlled compliantrecirculating dialysate loop utilizing a sorbent cartridge 725 fordialysate regeneration and a sorbent cartridge bypass loop 723 forachieving equilibration between the dialysate and blood. Sorbentcartridge 725 can include sorbent materials and function as describedfor sorbent cartridges 100 and 110 shown in various FIG.'s. In general,the sorbent cartridge 725 is designed to remove certain species from thedialysate, such as but not limited to urea, creatinine, phosphate,sulfate, calcium, magnesium, potassium and beta-2-microglobulin. Bloodfrom a patient is directed along flow path 737 with pump 735 and entersa dialyzer 709 through a blood inlet flow path 701 and exits thedialyzer 709 through a blood outlet flow path 703 and is returned to thepatient. Dialysate is recirculated and regenerated in the dialysate flowloop 717. Dialysate exits the dialyzer 709 through the dialysate outletflow path 705 and a portion of the dialysate is removed from thedialysate flow loop 717 with a control pump 713 and is collected in areservoir 711. Dialysate is recirculated through the dialysate flow loopwith the dialysate pump 715 and continues to flow towards a sorbentcartridge 725 and a sorbent cartridge bypass loop 723. The position ofvalves 719, 721 and 739 determine if the dialysate flows through thesorbent cartridge 725 or through the sorbent cartridge bypass loop 723.Other valve positions and valve types are possible to achieve flowthrough either the sorbent cartridge 725 or the sorbent cartridge bypassloop 723 and are well known to those skilled in the art. Next, dialysateflows to pass a sensor system 727. Sensor system 727 may include asingle sensor or multiple sensors. The specific sensors making up sensorsystem 727 may include one or several of the following, but is notlimited to, a conductivity sensor, ion-selective sensor, osmoticpressure sensor, pH sensor, urea sensor, and creatinine sensor. Afterthe sensor system 727 the dialysate flows to pass a reconstitutionsystem 733 which acts to change the composition of the dialysate beforethe dialysate re-enters the dialyzer through the dialysate inlet flowpath 707. The reconstitution system 733 also functions to replacecertain species that are removed by the sorbent cartridge 725 such ascalcium, magnesium and potassium. The reconstitution system 733 as shownin FIG. 16 includes a reconstitution pump 729 and a reconstitutionreservoir 731. The reconstitution reservoir can contain, but is notlimited to, electrolyte solutions such as salts of calcium, magnesium,potassium, acetate, chloride and sodium, which will be added to thedialysate via pump 729 in order to change the chemical composition ofthe dialysate. The reconstitution system may also include multiple pumpsand reservoirs (not shown), each containing a different solution fordelivery to the dialysate flow loop 717. Other examples of chemicalspecies that can be delivered with the reconstitution system 733 includebicarbonate, glucose, and lactate. The reconstitution system 733 canalso include a reservoir containing water that will act to dilute theconcentration of species in the dialysate. In certain embodiments thesorbent cartridge 725 can consist of ion-exchange materials that willremove certain waste species in exchange for sodium. Therefore, in orderto maintain a certain dialysate sodium concentration it may becomenecessary to remove sodium from the dialysate by direct removal of thesodium, or by dilution of the sodium concentration by adding water tothe dialysate loop 717.

In certain embodiments for the system illustrated in FIG. 16 the volumeof the dialysate flow loop 717 can be less than 1 liter and as small as0.5 liters. The combination of using a controlled compliant flow path,along with a sorbent cartridge 725 for dialysate regeneration, waterfeed from the reconstitution system 733 for sodium management, and acontrol pump 713 for the removal of a certain volume of dialysate fromthe dialysate flow loop 717, allows the dialysate flow loop to have asmall volume. In certain embodiments the dialysate flow loop volume 717can be 0.5 liters or less.

FIG. 17 shows a flow diagram similar to the one in FIG. 16 , except itincludes a sorbent cartridge recirculation loop 751. The sorbentcartridge recirculation loop 751 includes a recirculating pump 741 thatrecirculates the dialysate remaining in the sorbent cartridge 725 whilethe dialysate from the dialysate flow loop 717 is directed through thesorbent cartridge bypass loop 723. The open or closed status of thetwo-way valves 719, 739 and 721 and operation of recirculating pump 741determine if dialysate will be recirculated through the sorbentcartridge recirculation loop 751, flow through the sorbent cartridgebypass loop 723 or flow through the sorbent cartridge 725. For example,by closing valves 719 and 739 and opening valve 721 and operating pump741 the dialysate contained in the sorbent cartridge 725 will berecirculated through the sorbent cartridge recirculation loop 751 andthe remaining dialysate in the dialysate flow loop 717 will flow throughthe sorbent cartridge bypass loop 723. It will be apparent to thoseskilled in the art that other valve positions and valve types, such asthree-way valves, can be utilized to achieve the same outcomes. Incertain embodiments, where the sorbent cartridge 725 is configured, asdescribed above, to direct various flow paths to a conductivity sensorin order to measure urea and/or calcium and magnesium concentration, itcan be beneficial to recirculate the dialysate remaining in the sorbentcartridge 725 in order to remove certain species still present in thedialysate contained in the sorbent cartridge 725. Removal of anyresidual species present in the dialysate contained in the sorbentcartridge 725, by recirculation through the sorbent cartridgerecirculation loop 751 may improve the accuracy of concentrationmeasurements after dialysate equilibration with the blood has occurred.In certain embodiments the sorbent cartridge 725 can be of a size thatcan contain several hundred milliliters of dialysate, for example 100 to1000 milliters. Therefore, any remaining volume of dialysate containedin the sorbent cartridge 725 will contain a certain concentration ofspecies, for example urea, that has not been removed yet, and this urea,for example, will affect the concentration reading obtained using thesorbent cartridge sensor systems described above after dialysateequilibration has occurred with the blood. Continual recirculation ofthe dialysate with the sorbent cartridge recirculation loop 751 helpsensure complete removal of any residual species present in the dialysatecontained in the sorbent cartridge 725 during equilibration of thedialysate with the blood.

FIG. 18 shows a flow diagram similar to the one shown in FIG. 16 ,except it includes a dialyzer bypass flow path 767. The dialyzer bypassflow path 767 can be used to circulate dialysate through the sorbentcartridge 725 without having the dialysate pass through the dialyzer709. Two-way valves 747, 745 and 743 determine where the dialysate willflow. For example, by closing valves 745 and 743 and opening valve 747,the dialysate will flow through the dialyzer bypass flow path 767 andwill not flow through the dialyzer 709. It will be apparent to thoseskilled in the art that other valve positions and valve types, such asthree-way valves, can be utilized to achieve the same flow outcomes.Recirculating the dialysate through the sorbent cartridge 725 withoutpassing the dialysate through the dialyzer will completely removecertain species from the dialysate. After the complete removal ofcertain species from the dialysate, such as urea, the dialysate flow canbe directed back through the dialyzer and concentration changes overtime of certain species in the dialysate can be measured with sensorsystem 727 and used to determine the performance of the dialyzerthroughout the therapy and/or the decrease in concentration of certainspecies in the blood throughout the therapy.

FIG. 19 shows a flow diagram for a single-pass hemodialysis systemutilizing a bypass flow loop 759 to achieve periodic equilibrationbetween the dialysate and blood. Prepared dialysate enters the systemthrough flow path 753 by operation of dialysate pump 757 and continuesto pass sensor system 727. The dialysate continues through the dialyzer709 as described before for FIG. 16 . After exiting the dialyzer 709through the dialysate outlet flow path 705 the dialysate exits thesystem through flow path 765. By closing valves 755 and 763 and openingvalve 761 the dialysate will be directed through the dialysaterecirculation loop 759 and will eventually equilibrate with the bloodflowing through the dialyzer 709, thereby allowing the determination ofblood concentration levels for certain species by utilization of sensorsystem 727. The dialysate recirculation loop 759 can be prepared to havea small volume, around 500 milliliters or less to minimize the timerequired to reach equilibration between the dialysate and blood.

FIGS. 20 through 23 illustrate the effect of various parameters onequilibration time between dialysate and blood. The governing equationsused to generate the graphs are derived from a total and differentialmass balance on a species between the dialysate and blood. Equation 6shows the total mass balance for an arbitrary species at any given timeduring equilibration:V _(D) ·C _(D) +V _(B) ·C _(B) =V _(B) ·C _(Bo)  [Eq. 6]where V_(D) is dialysate volume in liters, C_(D) is dialysateconcentration at time tin mg/dL, V_(B) is the patient volume for aparticular species in liters. For urea V_(B) would be equal to the ureadistribution volume described above. C_(B) is the blood concentration inmg/dL at time t and C_(Bo) is the blood concentration at a time definedas zero in mg/dL. Equation 7 shows the differential mass balance for thedialysate:V _(D)·(dC _(D) /dt)=K(C _(B) −C _(D))  [Eq. 7]where dC_(D)/dt is the differential change in dialysate concentrationwith time and K is the dialyzer clearance for an arbitrary species asdescribed above. The use of equations 6 and 7 assumes instantaneoustransfer of species between the blood compartment of the body andextra-vascular compartments and assumes the generation of species isnegligible and removal of species by means other than dialysis are alsonegligible. Equations 6 and 7 also assume no filtration is occurringacross the dialyzer and that the dialyzer clearance K does not depend onthe concentration of blood or dialysate. Equations 6 and 7 can besolved, assuming the initial dialysate concentration is zero to yieldthe following non-linear equation 8:C _(D) =C _(Bo)[(1/V _(D))/(1/V _(B)+1/V _(D))][1−e{circumflex over( )}[−Kt(1/V _(B)+1/V _(D))]]  [Eq. 8]Also, the concentration of blood during equilibration can be determinedby rearrangement of Eq. 8 and the total mass balance equation 6.

FIG. 20 is generated using the equations described above to illustratethe change in dialysate and blood concentration of urea duringequilibration. The results are shown for a 6 liter dialysate volume, adialyzer clearance of 290 milliliters/minute and a starting blood urea,BUN concentration of 70 mg/dL. The dialyzer clearance of 290milliliters/minute is used based on a blood flow of 400 ml/min and adialysate flow of 400 milliliters/minute and a dialyzer size of 1.5meters squared. Likewise, FIG. 21 shows the change in dialysateconcentration and blood over time for urea during equilibrium with thesame conditions as for FIG. 20 , except with a dialysate volume of 0.5liters. The time to reach equilibration between blood and dialysate with6 liters of dialysate takes over 30 minutes compared to less than 5minutes if the dialysate volume is 0.5 liters, illustrating thesignificant advantage to having a small dialysate volume in terms ofminimizing equilibration time. FIGS. 20 and 21 also show the bloodconcentration of urea over time during equilibration. As shown in FIG.21 the blood concentration does not change by a significant amountduring equilibration resulting in an accurate determination of theactual blood concentration. However, FIG. 20 shows a significant declinein blood concentration during equilibration, which will result in aninaccurate determination of blood concentration at the time point ofinterest. FIG. 22 also illustrates the effect of dialysate volume on thechange in dialysate concentration of urea over time during equilibrationwith blood. The data shown in FIG. 22 is generated under the sameconditions as the data in FIGS. 20 and 21 , except dialysate volumes of1 liter and 3 liters are also shown. FIG. 22 also illustrates thesignificant effect dialysate volume has on equilibration time, even atvolumes as low as 1 liter. Therefore, there is significant advantage tohaving a dialysate flow path with a small volume of 0.5 liters or less,as described in various embodiments of the invention.

FIG. 23 shows the effect of dialysate flow rate on the change indialysate concentration over time during equilibration with blood. Thedata is generated assuming a starting blood urea BUN concentration of 70mg/dL, a blood flow rate of 400 ml/min, a 1.5 meter square dialyzer anda dialysate volume of 0.5 liters. The dialyzer clearance at dialysateflow rates of 50, 100, 200 and 400 ml/min are assumed to be 50, 100, 190and 290 ml/min, respectively. FIG. 23 illustrates the significant effectdialysate flow rate has on equilibration time. For example, a dialysateflow rate of 100 ml/min requires 15 minutes for equilibration, comparedto only 5 minutes required for a dialysate flow rate of 400 ml/min.Therefore, increasing the dialysate flow rate during equilibration willreduce the time to reach equilibrium. For example, if a dialysis therapyrequires a dialysate flow rate of 100 ml/min, due to capacity and flowlimitations of the sorbent cartridge, during equilibration the dialysateflow rate can be increased above 100 ml/min without affecting thesorbent cartridge because the dialysate flow will not flow through thesorbent cartridge. Likewise, the blood flow can also be increased duringequilibration, which will increase the dialyzer clearance, K, andthereby decrease the equilibration time. In some cases it may beneficialto increase the blood and dialysate flow, in order to minimize theequilibration time.

The filtration rate across the dialyzer will also decrease the time toreach equilibration. Therefore, continuing to perform ultrafiltration onthe patient during the equilibration period will help decrease theequilibration time. In FIGS. 16, 17 and 18 the control pump 713 can beused to provide ultrafiltration across the dialyzer. In certainembodiments the ultrafiltration rate can be increased duringequilibration to achieve a further reduction in equilibration time.

Another feature of the systems described for FIGS. 16, 17 and 18 , isthe use of a conductivity sensor as part of the sensor system 727. Aconductivity sensor can be used in several ways. First, the conductivityof the dialysate can be monitored during equilibration to determine whenequilibration is reached. In general the conductivity of the dialysateis a measure of the sodium concentration because it is the majorconductive species present. If the blood sodium concentration differsfrom the dialysate sodium concentration, the conductivity of thedialysate can be monitored until a plateau is reached, which wouldindicate that the sodium concentration of the blood has equilibratedwith the sodium concentration of the dialysate. Because sodium and ureaoccupy approximately the same volume in a patient and transfer acrossthe dialyzer at similar rates, equilibration of sodium will alsoindicate equilibration with urea. The same is also true for calcium,magnesium, potassium and chloride with respect to sodium and urea. Incertain cases the dialysate sodium concentration and blood sodiumconcentration will be close to the same value, which would lead to anegligible change in dialysate conductivity during equilibration. Insuch cases the dialysate sodium concentration can be temporarilyincreased by adding a sodium bolus to the dialysate with thereconstitution system 733 described above for FIGS. 16, 17 and 18 .Likewise the reconstitution system 733 can also temporarily decrease thesodium concentration of the dialysate by adding water to dilute thedialysate. The temporary change in sodium concentration of the dialysatewill result in a sodium concentration difference between the blood anddialysate and ultimately a conductivity difference that can be monitoredduring equilibration to determine when equilibration is complete.

Another advantage of the equilibration method is the ability todetermine a patient's pre-dialysis blood sodium concentration. In somecases it is beneficial to the patient if their blood sodiumconcentration before and after a dialysis session remains the same,which can result in less fluid gain between dialysis sessions. Byutilizing the equilibration method at the start of a dialysis session, apatient's initial blood conductivity can be determined. However, asshown, accurate determination of the patient's blood conductivityrequires minimization of the equilibration time between the blood anddialysate, which can be achieved utilizing several of the methodsdescribed for certain embodiments including low volume dialysate,increased dialysate and blood flow rates, and continuation ofultrafiltration during the equilibration. As stated before theconductivity of the blood and dialysate is approximately equal to thesodium concentration of the blood and dialysate. Therefore, theconductivity of the blood at the start and end of a dialysis session canbe determined using the equilibration techniques described. The therapycan then be adjusted by changing the delivery of solutions with thereconstitution system 733 in order to ensure the blood conductivity atthe end of the session matches the conductivity at the beginning of thesession, as determined with the equilibration method. The sensor system727 can also include a sodium sensor for measuring sodium directly, suchas an ion-selective electrode for sodium. The patient's initialpre-dialysis sodium concentration, pH, conductivity values, ammonium ionor urea concentrations, can also be used to set target values for anyone of conductivity, pH, sodium concentration, ammonium ion, or ureavalues for the dialysate to be used during the dialysis session. In somecases the dialysate conductivity can be controlled with a closed-loopsystem between the conductivity sensor and the reconstitution system733. Sensor types, such as ion-selective electrodes and pH can be usedin a similar manner as described herein for closed-loop control and tomake measurements by calculating a difference based on any one of pH,sodium and urea concentrations, and ammonium ion concentrations.

FIG. 24 shows a diagram for a sorbent cartridge design that includesbuilt-in conductivity electrodes 603 and 605. The sorbent cartridge 601is similar to sorbent cartridge 100 described for FIG. 1 , except forthe addition of conductivity electrodes 603 and 605. Dialysate entersthe sorbent cartridge 601 through the inlet flow path 301 and exitsthrough the outlet flow path 302 after passing through multiple sorbentmaterial layers 102, 103, 104, and 105 as described for FIG. 1 .However, the number of sorbent materials contained in the sorbentcartridge can be varied and the position of the sorbent materials can bechanged. As shown in FIG. 24 the sorbent materials are in discretelayers separated by interfaces 625, 627 and 629. The interface 625represents where the first sorbent material 102 ends and the secondsorbent material 103 begins. Likewise, interface 627 represents wherethe second sorbent material 103 ends and the third sorbent material 104begins. Also, interface 629 represents where the third sorbent material104 ends and the fourth sorbent material 105 begins. Four or moresorbent layers and the required number of interface layers arecontemplated by the present invention. A central axis 606 is shown whichrepresents a straight line, parallel to the direction of flow throughthe sorbent cartridge 601, to which the sorbent cartridge 601 issymmetrical. The electrode pair, 603 and 605, include one conductivitysensor that is built into the sorbent cartridge 601. The electrodes 603and 605 can be fastened through the wall of the sorbent cartridge 601.Various means for fastening the electrodes 603 and 605 can be envisionedand are well known to those of skill in the art. Non-limiting examplesof fastening methods may include welding and adhesive bonding, andmechanical fixation among others. The electrodes may also be fastened ateach end of the sorbent cartridge as opposed to the sides, which is theconfiguration shown in FIG. 24 . The electrodes 603 and 605 have anactive electrode head 631 and 633, respectively. An electricalconductivity measurement occurs when a potential is applied across theelectrode heads 631 and 633 and the current is measured. Theconductivity can then be calculated with Ohm's law (V=IR), where V isthe applied potential, I is the measured current and R is theresistivity, which is equal to the inverse of the conductivity. Theelectrode heads 631 and 633 can be made from various materials known tothose with skill in the art including, but not limited to platinum,platinum-iridium, titanium, gold-plated nickel, and graphite and can bepositioned at any varying radii from the central axis 606. For example,electrode heads 631 and 633 can be positioned near or at a perimeter,periphery or circumference of a sorbent layer, or near or on the centralaxis 606. In embodiments where the sorbent layer has a circumference asmeasured from the central axis 606, the electrode heads can bepositioned at any one of 7r/8, 3r/4, r/2, r/3, r/4, r/5, r/8, r/16,r/32, and r/64 where r is the radius measured from the central axis 606.

The portion of the electrodes 603 and 605 leading out of the sorbentcartridge 601 can be made from the same material as the electrode head,or other conductive materials and can serve to both stabilize theelectrode heads 631 and 633 within the sorbent cartridge 601 and providea path to apply the potential and measure the current across theelectrode heads 631 and 633. The potential can be applied by varioussources and methods well known to those of skill in the art, includingwith an external power supply. The resulting current can be measured byvarious ways well known to those of skill in the art, including with anammeter. It is also possible to determine the conductivity by applying acurrent across the electrode heads 631 and 633 and measuring theresulting potential.

The electrode heads 631 and 633 shown in FIG. 24 can be placed invarious positions within the sorbent cartridge 601. As shown in FIG. 24both electrode heads 631 and 633 are positioned close to the centralaxis 606 as shown in the side-view and end-view of FIG. 24 . Theelectrode heads as positioned in FIG. 24 , will measure conductivityacross a distance perpendicular to the central axis 606. The electrodeheads 631 and 633 are also located in sorbent material 102 nearinterface 625. However, other positions for the electrode heads 631 and633 are considered. For example, the electrode heads 631 and 633 can beplaced in any sorbent material layer and at any distance away from theinterface. Also, the electrode heads 631 and 633 can be located anyposition from the central axis. The distance between the electrode heads631 and 633 can also be varied. In some cases it is beneficial to have aminimum distance between the electrode heads 631 and 633 in order toavoid local conductivity measurements that may be high or low, comparedto other locations within the sorbent cartridge. In certain embodiments,the electrode heads 631 and 633 are positioned in the same sorbentmaterial layer. Finally, multiple electrodes may be placed throughoutthe sorbent cartridge 601 in order to measure multiple conductivities atmultiple positions within the sorbent cartridge 601. In the case ofmultiple electrodes present in the sorbent cartridge 601 a multiplexercan be used.

FIG. 25 shows a sorbent cartridge 601 with electrodes 603 and 605similar to the ones shown in FIG. 24 , except the electrode heads 631and 633 are positioned to measure conductivity across a distanceparallel to the central axis 606. The electrode heads 631 and 633 canalso be placed in the various positions described above with referenceto FIG. 24 , for example, at different material layers in the sorbentcartridge The positioning of the electrode heads 640 and 641 fartherapart allows the conductivity to be measured across a distance parallelto the direction of flow through the sorbent cartridge and can be usedto determine changes in capacity of a particular sorbent material andcumulative removal of species from the dialysate.

FIG. 26 is similar to FIG. 25 except the distance between the electrodeheads 640 and 641 is farther apart. The electrode heads 640 and 641 canalso be placed in the various positions described above with referenceto FIG. 24 .

FIG. 27 is similar to FIG. 26 , except several electrodes 609A, 609B,609C, 611A and 611B are shown. This configuration allows multipleelectrode pairs to be selected resulting in multiple conductivitymeasurements. For example, a potential can be applied across electrodes609A and 609B and the conductivity measured or a potential can beapplied across electrodes 609A and 611A. Other combination of electrodescan be envisioned to gather specific measurements as may be requiredbetween the various material layers in the sorbent.

FIG. 28 is similar to FIG. 27 , except the electrodes are made out ofmesh and function to not only measure conductivity as described for FIG.27 , but also function to provide flow redistribution as dialysate flowsthrough the sorbent cartridge 608 and provide separation between thesorbent layers. The mesh electrodes can have a mesh size of 1 to 100microns and the mesh opening can be configured in various geometries,such as squares (as shown in FIG. 28 side-view), circles or rectangles(not shown).

FIG. 29 shows different electrode designs that can be used inembodiments described above with reference to FIGS. 24, 25, 26 and 27 .It will be obvious to those skilled in the art that other electrodedesigns can be used. Disc electrodes 603A and 605A have an electrodehead 649 and 650 in the shape of a disc. Rod electrodes 603B and 605Brefer to electrodes in the shape of a rod or cylinder, with one endfunctioning as an electrode head 651 and 652. Sheet electrodes 603C and605C refer to an electrode with an electrode head 653 and 654 in theshape of a sheet. The sheets can be square, rectangular, circular orother solid planar geometries. The mesh electrodes 603D and 605D referto an electrode with an electrode head 655 and 656 consisting of a mesh,where a mesh is the same as that described for a mesh electrode. Antennaelectrodes 603E and 605E refer to an electrode with an electrode head657 and 658 in the shape of an antenna, where the antenna shape refersto a serpentine structure of conductive wires or strips. Pin electrodes603F and 605F refer to a rod electrode with a small diameter and anelectrode head 659 and 660. Other electrodes and electrode headgeometries known within the art are contemplated and can be used in thepresent invention.

FIG. 30 shows a sorbent cartridge 610 with electrode strips 621 and 622built into the wall of the sorbent cartridge 610. The electrode strips621 and 622 contain active electrode areas 617, 618, 619 and 620 thatcan be used in various pair configurations to measure conductivity. Theelectrode strips 621 and 622 can be built into the wall of the sorbentcartridge by bonding, welding or other methods well known to those ofskill in the art. The electrode strips can also include flex circuits.The sorbent cartridge could also contain a single electrode strip thatwraps around the whole perimeter of the sorbent cartridge wall. The useof electrode strips built into the wall of a sorbent cartridgesimplifies the construction and incorporation of electrodes into asorbent cartridge. The electrode strips can be connected external to thesorbent cartridge in order to apply a potential and measure currentacross active electrode areas.

The FIG.'s and specific examples provided herein illustrate a possibleembodiment of the invention and are non-limiting with respect to thespecific physical geometries of the various components depicted in theillustrations. It will be apparent to one skilled in the art thatvarious combinations and/or modifications can be made in the systems andmethods described herein depending upon the specific needs foroperation. Moreover, features illustrated or described as being part ofone embodiment may be used on another embodiment to yield a stillfurther embodiment.

What is claimed is:
 1. A system, comprising; a recirculation flow pathin communication with a dialyzer; the recirculation flow path comprisingat least one pump and at least one sensor measuring at least one fluidcharacteristic; a sorbent cartridge flow path; the sorbent cartridgeflow path in communication with the dialyzer and containing at least onesorbent cartridge; and a processor in communication with the at leastone sensor; the processor programmed to obtain the at least one fluidcharacteristic from the at least one sensor while dialysate in therecirculation flow path is in equilibrium with blood of the patient; andto determine a pre-dialysis blood solute level of at least one solute ina patient based on the at least one fluid characteristic.
 2. The systemof claim 1, the processor further programmed to control at least onevalve to direct dialysate through the recirculation flow path to obtaindata from the at least one sensor; and to direct dialysate through thesorbent cartridge flow path to deliver treatment to the patient.
 3. Thesystem of claim 1, wherein the processor is programmed to determine thepre-dialysis blood solute level of the at least one solute at abeginning of a dialysis session.
 4. The system of claim 3, the systemfurther comprising a reconstitution system in the sorbent cartridge flowpath downstream of the sorbent cartridge; the processor programmed tocontrol the reconstitution system based on the pre-dialysis blood solutelevel of the at least one solute.
 5. The system of claim 1, wherein theprocessor is programmed to determine the pre-dialysis blood solute levelof the at least one solute at an end of a dialysis session.
 6. Thesystem of claim 1, wherein the processor is programmed to determine thepre-dialysis blood solute level of the at least one solute at abeginning of a dialysis session and at an end of the dialysis session.7. The system of claim 6, wherein the processor is programmed todetermine a change in blood solute level of the at least one soluteduring the dialysis session.
 8. The system of claim 1, wherein the atleast one solute comprises sodium.
 9. The system of claim 1, wherein theat least one solute comprises urea.
 10. The system of claim 1, whereinthe at least one sensor comprises a conductivity sensor.
 11. The systemof claim 1, wherein the at least one sensor comprises an ion selectiveelectrode.
 12. The system of claim 1, wherein the at least one sensorcomprises an osmotic pressure sensor.
 13. The system of claim 1, whereinthe at least one sensor comprises a pH sensor.
 14. The system of claim1, wherein the at least one sensor comprises a creatinine sensor. 15.The system of claim 1, the processor programmed to determine whetherdialysate in the recirculation flow path is in equilibrium with blood ofthe patient.
 16. The system of claim 1, wherein the at least one sensormeasures the at least one fluid characteristic in both the recirculationflow path and the sorbent cartridge flow path.
 17. The system of claim1, further comprising a sorbent cartridge recirculation flow path; thesorbent cartridge recirculation flow path comprising the sorbentcartridge, with the proviso that the sorbent cartridge recirculationflow path does not include the dialyzer.
 18. The system of claim 1, theprocessor programmed to set at least one target value for therapy basedon the at least one fluid characteristic at a start of a dialysissession.
 19. The system of claim 18, wherein the at least one targetvalue for therapy comprises at least one of sodium concentration, pH,conductivity, and/or ammonium ion or urea concentrations.
 20. The systemof claim 10, the system further comprising a reconstitution system inthe sorbent cartridge flow path downstream of the sorbent cartridge; theprocessor programmed to control the reconstitution system based on theat least one target value for therapy.